Kristi Fan - Academia.edu (original) (raw)

Papers by Kristi Fan

Research paper thumbnail of Design and Synthesis of 5,5′-Disubstituted Aminohydantoins as Potent and Selective Human β-Secretase (BACE1) Inhibitors

Journal of Medicinal Chemistry, 2010

The identification of small molecule aminohydantoins as potent and selective human beta-secretase... more The identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC(50) value for BACE1 of 10 nM and exhibited comparable cellular activity (EC(50) = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (p < 0.001).

Research paper thumbnail of Aminoimidazoles as Potent and Selective Human β-Secretase (BACE1) Inhibitors

Journal of Medicinal Chemistry, 2009

The identification of small molecule aminoimidazoles as potent and selective human beta-secretase... more The identification of small molecule aminoimidazoles as potent and selective human beta-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsin D, renin, and pepsin. Our design strategy was supported by molecular modeling studies based on the cocrystal structure of the HTS-hit 3 in the BACE1 active site. These strategies enabled us to integrate pyridine and pyrimidine groups on 3 extending deep into the S3 region of the BACE1 binding pocket and enhancing the ligand's potency. Compound (R)-37 displayed an IC50 value for BACE1 of 20 nM, cellular activity of 90 nM, and >100-fold selectivity over related aspartyl proteases. Acute oral administration of (R)-37 at 30 mg/kg resulted in a significant 71% reduction of plasma Abeta40 measured at the 6 h time point in a Tg2576 mouse model (p < 0.001).

Research paper thumbnail of Acylguanidines as Small-Molecule β-Secretase Inhibitors

Journal of Medicinal Chemistry, 2006

BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abet... more BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).

Research paper thumbnail of Corrections to Aminoimidazoles as Potent and Selective Human β-Secretase (BACE1) Inhibitors

Journal of Medicinal Chemistry, 2010

Abstract: The identification of small molecule aminoimidazoles as potent and selective human β-se... more Abstract: The identification of small molecule aminoimidazoles as potent and selective human β-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, ...

Research paper thumbnail of Discovery of Begacestat, a Notch-1-Sparing γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease

Journal of Medicinal Chemistry, 2008

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg... more SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.

Research paper thumbnail of High throughput artificial membrane permeability assay for blood–brain barrier

European Journal of Medicinal Chemistry, 2003

The recent advances in high throughput screening for biological activities and combinatorial chem... more The recent advances in high throughput screening for biological activities and combinatorial chemistry have greatly expanded the number of drug candidates. Rapid screening for BBB penetration potential early in drug discovery programs provides important information for compound selection and guidance of synthesis for desirable CNS properties. In this paper, we discuss a modification of the parallel artificial membrane permeation assay (PAMPA) for the prediction of blood Á/brain barrier penetration (PAMPA-BBB). The assay was developed with 30 structurally diverse commercial drugs and validated with 14 Wyeth Research compounds. The PAMPA-BBB assay has the advantages of: predicting passive blood Á/brain barrier penetration with high success, high throughput, low cost, and reproducibility.

Research paper thumbnail of Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery—Building chiral technology toolboxes

Chirality, 2007

The application of Chiral Technology, or the (extensive) use of techniques or tools for the deter... more The application of Chiral Technology, or the (extensive) use of techniques or tools for the determination of absolute stereochemistry and the enantiomeric or chiral separation of racemic small molecule potential lead compounds, has been critical to successfully discovering and developing chiral drugs in the pharmaceutical industry. This has been due to the rapid increase over the past 10-15 years in potential drug candidates containing one or more asymmetric centers. Based on the experiences of one pharmaceutical company, a summary of the establishment of a Chiral Technology toolbox, including the implementation of known tools as well as the design, development, and implementation of new Chiral Technology tools, is provided. Chirality 19:658-682, 2007. V V C 2007 Wiley-Liss, Inc. KEY WORDS: Chiral Technology; chiral separations; enantiomeric separations; determination of absolute stereochemistry; supercritical fluid chromatography; asymmetric transformations using enzymes; chiral salt resolution; vibrational circular dichroism; electronic circular dichroism; exciton coupling; optical rotation; modified Mosher's or Trost NMR method; chiral liquid crystal NMR asymmetric transformations, but not asymmetric transformations themselves. The terms Chiral Technology and Chirotechnology have often been used as a general category for asymmetric transformations using enzymes, chiral building blocks, chiral auxiliaries, and chiral catalysts, as well as chiral salt resolution. 1-13 Carl Balibar is currently at Harvard

Research paper thumbnail of New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: Exploring the S2′ region

Bioorganic & Medicinal Chemistry Letters, 2011

The proteolytic enzyme b-secretase (BACE1) plays a central role in the synthesis of the pathogeni... more The proteolytic enzyme b-secretase (BACE1) plays a central role in the synthesis of the pathogenic b-amyloid in Alzheimer's disease. SAR studies of the S2 0 region of the BACE1 ligand binding pocket with pyrazolyl and thienyl P2 0 side chains are reported. These analogs exhibit low nanomolar potency for BACE1, and demonstrate >50-to 100-fold selectivity for the structurally related aspartyl proteases BACE2 and cathepsin D. Small groups attached at the nitrogen of the P2 0 pyrazolyl moiety, together with the P3 pyrimidine nucleus projecting into the S3 region of the binding pocket, are critical components to ligand's potency and selectivity. P2 0 thiophene side chain analogs are highly potent BACE1 inhibitors with excellent selectivity against cathepsin D, but only modest selectivity against BACE2. The cell-based activity of these new analogs tracked well with their increased molecular binding with EC 50 values of 0.07-0.2 lM in the ELISA assay for the most potent analogs.

Research paper thumbnail of Molecular-modeling based design, synthesis, and activity of substituted piperidines as γ-secretase inhibitors

Bioorganic & Medicinal Chemistry Letters, 2005

AlzheimerÕs disease (AD) is a debilitating disease widely thought to be associated with the accum... more AlzheimerÕs disease (AD) is a debilitating disease widely thought to be associated with the accumulation of beta amyloid (Ab) in the brain. Inhibition of c-secretase, one of the enzymes responsible for Ab production, may be a useful strategy for the treatment of AD. Described below is a series of c-secretase inhibitors designed from a scaffold identified by a ROCS [J. Comput. Chem. 1996, 17, 1653 search of the corporate database.

Research paper thumbnail of Acylguanidine inhibitors of β-secretase: Optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets

Bioorganic & Medicinal Chemistry Letters, 2008

Proteolytic cleavage of amyloid precursor protein by b-secretase (BACE-1) and c-secretase leads t... more Proteolytic cleavage of amyloid precursor protein by b-secretase (BACE-1) and c-secretase leads to formation of b-amyloid (Ab) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of Ab and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S 1 and S 2 0 pockets leading to submicromolar BACE-1 inhibitors.

Research paper thumbnail of Novel pyrrolyl 2-aminopyridines as potent and selective human β-secretase (BACE1) inhibitors

Bioorganic & Medicinal Chemistry Letters, 2010

à Abbreviations. AD, Alzheimer's disease; Ab, beta-amyloid peptide, APP, b-amyloid precursor prot... more à Abbreviations. AD, Alzheimer's disease; Ab, beta-amyloid peptide, APP, b-amyloid precursor protein; BACE, b-site APP cleaving enzyme; FRET, fluorescence resonance energy transfer; ELISA, enzyme-linked immune sandwich assay; CHO, Chinese hamster ovary. Atomic coordinates of the BACE1 crystal structure with compounds 32 (3L3A) and 44 (3L38) have been deposited in the Protein Data Bank, Research

Research paper thumbnail of Synthesis and SAR of bis-statine based peptides as BACE 1 inhibitors

Bioorganic & Medicinal Chemistry Letters, 2004

A new series of bis-statine based peptidomimetic inhibitors of human beta-secretase (BACE 1) was ... more A new series of bis-statine based peptidomimetic inhibitors of human beta-secretase (BACE 1) was developed by structure-based modification of the three regions to the initial lead 3: an N-terminus, a central bis-statine core, and a C-terminus. Introduction of a 4-aminomethylbenzoic acid on the C-terminus resulted in a potent BACE 1 inhibitor with an IC50 value of 21 nM. The general requirements for the optimal substrate-enzyme interaction are disclosed herein.

Research paper thumbnail of Discovery and initial optimization of 5,5′-disubstituted aminohydantoins as potent β-secretase (BACE1) inhibitors

Bioorganic & Medicinal Chemistry Letters, 2010

a b s t r a c t pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibito... more a b s t r a c t pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S 1 to the S 3 pocket.

Research paper thumbnail of Di-substituted pyridinyl aminohydantoins as potent and highly selective human β-secretase (BACE1) inhibitors

Bioorganic & Medicinal Chemistry, 2010

The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as... more The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as bsecretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cellbased (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500Â) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2 0 pocket (BACE1 Pro 70 changed to BACE2 Lys 86 ) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand's affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC 50 value for BACE1 of 10 nM, and exhibited cellular activity with an EC 50 value of 130 nM in the ELISA assay.

Research paper thumbnail of Ion Channel Screening Plates: Design, Construction, and Maintenance

ASSAY and Drug Development Technologies, 2010

Ion channels have provided a diverse set of therapeutic targets across all areas of the pharmaceu... more Ion channels have provided a diverse set of therapeutic targets across all areas of the pharmaceutical industry. Many companies are pursuing this unique class of targets for areas of unmet medical need such as neuropathic and inflammatory pains. In the past, focused library screening sets had been designed for CNS and kinase targets. Our investigations were aimed at creating a similar dynamic screening set enriched for compounds targeting ion channels to aid screening efforts of this important class of targets. The key advantages of this approach for ion channel targets would be: (1) to identify tool compounds for novel targets and assist in assay validation, (2) to serve as a focused screen for non-384-well adaptable targets, and (3) to jump start a particular program, that is, catch-up to competition for validated, well-known targets.

Research paper thumbnail of Investigation of the critical amino acids in the BACE1 binding site that interact with small molecule inhibitors using a novel radioligand and X-ray crystallography

Alzheimer's & Dementia, 2009

Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 5, Issue... more Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 5, Issue 4, Pages P429, July 2009, Authors:Warren D. Hirst; Katie Kubek; Jonathan Bard; James Turner; Kristi Fan; Michael Malamas; Peter H. Reinhart; Albert J. Robichaud. ...

Research paper thumbnail of P2-481: Small molecule BACE-1 inhibitors are potent, selective and orally active

Alzheimer's & Dementia, 2008

... Michael Malamas; Jim Erdei; Iwan Gunawan; Albert Robichaud; Jim Turner; Yun Hu; Erik Wagner; ... more ... Michael Malamas; Jim Erdei; Iwan Gunawan; Albert Robichaud; Jim Turner; Yun Hu; Erik Wagner; Suzan Aschmies; Tom Comery; Kristi Fan; Rajiv Chopra; Ron Magolda; Menelas Pangalos; Peter Reinhart; David Riddell; Steve Jacobsen; Magid Abou-Gharbia; Jonathan Bard. ...

Research paper thumbnail of Design and synthesis of aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors with enhanced brain permeability

The identification of small molecule aminohydantoins as potent and selective human β-secretase in... more The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogs exhibit good brain permeability (40-70%), low nanomolar potency for BACE1, and demonstrate >100-fold selectivity for the structurally related aspartyl proteases cathepsin D, renin and pepsin. Alkyl and alkoxy groups at the meta-position of the P1 phenyl, which extend toward the S3 region of the enzyme, have contributed to the ligand's reduced affinity for the efflux transporter protein P-gp, and decreased topological polar surface area, thus resulting in enhanced brain permeability. A fluorine substitution at the para-position of the P1 phenyl has contributed to 100-fold decrease of CYP3A4 inhibition and enhancement of compound metabolic stability. The plasma and brain protein binding properties of these new analogs are affected by substitutions at the P1 phenyl moiety. Higher compound protein binding was observed in the brain than in the plasma. Two structurally diverse potent BACE1 inhibitors (84 and 89) reduced 30% plasma Aβ40 in the Tg2576 mice in vivo model at 30 mg/kg p.o..

Research paper thumbnail of Comparison of Several Molecular Docking Programs: Pose Prediction and Virtual Screening Accuracy

Journal of Chemical Information and Modeling, 2009

Molecular docking programs are widely used modeling tools for predicting ligand binding modes and... more Molecular docking programs are widely used modeling tools for predicting ligand binding modes and structure based virtual screening. In this study, six molecular docking programs (DOCK, FlexX, GLIDE, ICM, PhDOCK, and Surflex) were evaluated using metrics intended to assess docking pose and virtual screening accuracy. Cognate ligand docking to 68 diverse, high-resolution X-ray complexes revealed that ICM, GLIDE, and Surflex generated ligand poses close to the X-ray conformation more often than the other docking programs. GLIDE and Surflex also outperformed the other docking programs when used for virtual screening, based on mean ROC AUC and ROC enrichment values obtained for the 40 protein targets in the Directory of Useful Decoys (DUD). Further analysis uncovered general trends in accuracy that are specific for particular protein families. Modifying basic parameters in the software was shown to have a significant effect on docking and virtual screening results, suggesting that expert knowledge is critical for optimizing the accuracy of these methods.

Research paper thumbnail of Design and Synthesis of 5,5′-Disubstituted Aminohydantoins as Potent and Selective Human β-Secretase (BACE1) Inhibitors

Journal of Medicinal Chemistry, 2010

The identification of small molecule aminohydantoins as potent and selective human beta-secretase... more The identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC(50) value for BACE1 of 10 nM and exhibited comparable cellular activity (EC(50) = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (p < 0.001).

Research paper thumbnail of Aminoimidazoles as Potent and Selective Human β-Secretase (BACE1) Inhibitors

Journal of Medicinal Chemistry, 2009

The identification of small molecule aminoimidazoles as potent and selective human beta-secretase... more The identification of small molecule aminoimidazoles as potent and selective human beta-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsin D, renin, and pepsin. Our design strategy was supported by molecular modeling studies based on the cocrystal structure of the HTS-hit 3 in the BACE1 active site. These strategies enabled us to integrate pyridine and pyrimidine groups on 3 extending deep into the S3 region of the BACE1 binding pocket and enhancing the ligand's potency. Compound (R)-37 displayed an IC50 value for BACE1 of 20 nM, cellular activity of 90 nM, and >100-fold selectivity over related aspartyl proteases. Acute oral administration of (R)-37 at 30 mg/kg resulted in a significant 71% reduction of plasma Abeta40 measured at the 6 h time point in a Tg2576 mouse model (p < 0.001).

Research paper thumbnail of Acylguanidines as Small-Molecule β-Secretase Inhibitors

Journal of Medicinal Chemistry, 2006

BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abet... more BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).

Research paper thumbnail of Corrections to Aminoimidazoles as Potent and Selective Human β-Secretase (BACE1) Inhibitors

Journal of Medicinal Chemistry, 2010

Abstract: The identification of small molecule aminoimidazoles as potent and selective human β-se... more Abstract: The identification of small molecule aminoimidazoles as potent and selective human β-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, ...

Research paper thumbnail of Discovery of Begacestat, a Notch-1-Sparing γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease

Journal of Medicinal Chemistry, 2008

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg... more SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.

Research paper thumbnail of High throughput artificial membrane permeability assay for blood–brain barrier

European Journal of Medicinal Chemistry, 2003

The recent advances in high throughput screening for biological activities and combinatorial chem... more The recent advances in high throughput screening for biological activities and combinatorial chemistry have greatly expanded the number of drug candidates. Rapid screening for BBB penetration potential early in drug discovery programs provides important information for compound selection and guidance of synthesis for desirable CNS properties. In this paper, we discuss a modification of the parallel artificial membrane permeation assay (PAMPA) for the prediction of blood Á/brain barrier penetration (PAMPA-BBB). The assay was developed with 30 structurally diverse commercial drugs and validated with 14 Wyeth Research compounds. The PAMPA-BBB assay has the advantages of: predicting passive blood Á/brain barrier penetration with high success, high throughput, low cost, and reproducibility.

Research paper thumbnail of Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery—Building chiral technology toolboxes

Chirality, 2007

The application of Chiral Technology, or the (extensive) use of techniques or tools for the deter... more The application of Chiral Technology, or the (extensive) use of techniques or tools for the determination of absolute stereochemistry and the enantiomeric or chiral separation of racemic small molecule potential lead compounds, has been critical to successfully discovering and developing chiral drugs in the pharmaceutical industry. This has been due to the rapid increase over the past 10-15 years in potential drug candidates containing one or more asymmetric centers. Based on the experiences of one pharmaceutical company, a summary of the establishment of a Chiral Technology toolbox, including the implementation of known tools as well as the design, development, and implementation of new Chiral Technology tools, is provided. Chirality 19:658-682, 2007. V V C 2007 Wiley-Liss, Inc. KEY WORDS: Chiral Technology; chiral separations; enantiomeric separations; determination of absolute stereochemistry; supercritical fluid chromatography; asymmetric transformations using enzymes; chiral salt resolution; vibrational circular dichroism; electronic circular dichroism; exciton coupling; optical rotation; modified Mosher's or Trost NMR method; chiral liquid crystal NMR asymmetric transformations, but not asymmetric transformations themselves. The terms Chiral Technology and Chirotechnology have often been used as a general category for asymmetric transformations using enzymes, chiral building blocks, chiral auxiliaries, and chiral catalysts, as well as chiral salt resolution. 1-13 Carl Balibar is currently at Harvard

Research paper thumbnail of New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: Exploring the S2′ region

Bioorganic & Medicinal Chemistry Letters, 2011

The proteolytic enzyme b-secretase (BACE1) plays a central role in the synthesis of the pathogeni... more The proteolytic enzyme b-secretase (BACE1) plays a central role in the synthesis of the pathogenic b-amyloid in Alzheimer's disease. SAR studies of the S2 0 region of the BACE1 ligand binding pocket with pyrazolyl and thienyl P2 0 side chains are reported. These analogs exhibit low nanomolar potency for BACE1, and demonstrate >50-to 100-fold selectivity for the structurally related aspartyl proteases BACE2 and cathepsin D. Small groups attached at the nitrogen of the P2 0 pyrazolyl moiety, together with the P3 pyrimidine nucleus projecting into the S3 region of the binding pocket, are critical components to ligand's potency and selectivity. P2 0 thiophene side chain analogs are highly potent BACE1 inhibitors with excellent selectivity against cathepsin D, but only modest selectivity against BACE2. The cell-based activity of these new analogs tracked well with their increased molecular binding with EC 50 values of 0.07-0.2 lM in the ELISA assay for the most potent analogs.

Research paper thumbnail of Molecular-modeling based design, synthesis, and activity of substituted piperidines as γ-secretase inhibitors

Bioorganic & Medicinal Chemistry Letters, 2005

AlzheimerÕs disease (AD) is a debilitating disease widely thought to be associated with the accum... more AlzheimerÕs disease (AD) is a debilitating disease widely thought to be associated with the accumulation of beta amyloid (Ab) in the brain. Inhibition of c-secretase, one of the enzymes responsible for Ab production, may be a useful strategy for the treatment of AD. Described below is a series of c-secretase inhibitors designed from a scaffold identified by a ROCS [J. Comput. Chem. 1996, 17, 1653 search of the corporate database.

Research paper thumbnail of Acylguanidine inhibitors of β-secretase: Optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets

Bioorganic & Medicinal Chemistry Letters, 2008

Proteolytic cleavage of amyloid precursor protein by b-secretase (BACE-1) and c-secretase leads t... more Proteolytic cleavage of amyloid precursor protein by b-secretase (BACE-1) and c-secretase leads to formation of b-amyloid (Ab) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of Ab and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S 1 and S 2 0 pockets leading to submicromolar BACE-1 inhibitors.

Research paper thumbnail of Novel pyrrolyl 2-aminopyridines as potent and selective human β-secretase (BACE1) inhibitors

Bioorganic & Medicinal Chemistry Letters, 2010

à Abbreviations. AD, Alzheimer's disease; Ab, beta-amyloid peptide, APP, b-amyloid precursor prot... more à Abbreviations. AD, Alzheimer's disease; Ab, beta-amyloid peptide, APP, b-amyloid precursor protein; BACE, b-site APP cleaving enzyme; FRET, fluorescence resonance energy transfer; ELISA, enzyme-linked immune sandwich assay; CHO, Chinese hamster ovary. Atomic coordinates of the BACE1 crystal structure with compounds 32 (3L3A) and 44 (3L38) have been deposited in the Protein Data Bank, Research

Research paper thumbnail of Synthesis and SAR of bis-statine based peptides as BACE 1 inhibitors

Bioorganic & Medicinal Chemistry Letters, 2004

A new series of bis-statine based peptidomimetic inhibitors of human beta-secretase (BACE 1) was ... more A new series of bis-statine based peptidomimetic inhibitors of human beta-secretase (BACE 1) was developed by structure-based modification of the three regions to the initial lead 3: an N-terminus, a central bis-statine core, and a C-terminus. Introduction of a 4-aminomethylbenzoic acid on the C-terminus resulted in a potent BACE 1 inhibitor with an IC50 value of 21 nM. The general requirements for the optimal substrate-enzyme interaction are disclosed herein.

Research paper thumbnail of Discovery and initial optimization of 5,5′-disubstituted aminohydantoins as potent β-secretase (BACE1) inhibitors

Bioorganic & Medicinal Chemistry Letters, 2010

a b s t r a c t pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibito... more a b s t r a c t pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S 1 to the S 3 pocket.

Research paper thumbnail of Di-substituted pyridinyl aminohydantoins as potent and highly selective human β-secretase (BACE1) inhibitors

Bioorganic & Medicinal Chemistry, 2010

The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as... more The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as bsecretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cellbased (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500Â) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2 0 pocket (BACE1 Pro 70 changed to BACE2 Lys 86 ) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand's affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC 50 value for BACE1 of 10 nM, and exhibited cellular activity with an EC 50 value of 130 nM in the ELISA assay.

Research paper thumbnail of Ion Channel Screening Plates: Design, Construction, and Maintenance

ASSAY and Drug Development Technologies, 2010

Ion channels have provided a diverse set of therapeutic targets across all areas of the pharmaceu... more Ion channels have provided a diverse set of therapeutic targets across all areas of the pharmaceutical industry. Many companies are pursuing this unique class of targets for areas of unmet medical need such as neuropathic and inflammatory pains. In the past, focused library screening sets had been designed for CNS and kinase targets. Our investigations were aimed at creating a similar dynamic screening set enriched for compounds targeting ion channels to aid screening efforts of this important class of targets. The key advantages of this approach for ion channel targets would be: (1) to identify tool compounds for novel targets and assist in assay validation, (2) to serve as a focused screen for non-384-well adaptable targets, and (3) to jump start a particular program, that is, catch-up to competition for validated, well-known targets.

Research paper thumbnail of Investigation of the critical amino acids in the BACE1 binding site that interact with small molecule inhibitors using a novel radioligand and X-ray crystallography

Alzheimer's & Dementia, 2009

Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 5, Issue... more Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 5, Issue 4, Pages P429, July 2009, Authors:Warren D. Hirst; Katie Kubek; Jonathan Bard; James Turner; Kristi Fan; Michael Malamas; Peter H. Reinhart; Albert J. Robichaud. ...

Research paper thumbnail of P2-481: Small molecule BACE-1 inhibitors are potent, selective and orally active

Alzheimer's & Dementia, 2008

... Michael Malamas; Jim Erdei; Iwan Gunawan; Albert Robichaud; Jim Turner; Yun Hu; Erik Wagner; ... more ... Michael Malamas; Jim Erdei; Iwan Gunawan; Albert Robichaud; Jim Turner; Yun Hu; Erik Wagner; Suzan Aschmies; Tom Comery; Kristi Fan; Rajiv Chopra; Ron Magolda; Menelas Pangalos; Peter Reinhart; David Riddell; Steve Jacobsen; Magid Abou-Gharbia; Jonathan Bard. ...

Research paper thumbnail of Design and synthesis of aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors with enhanced brain permeability

The identification of small molecule aminohydantoins as potent and selective human β-secretase in... more The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogs exhibit good brain permeability (40-70%), low nanomolar potency for BACE1, and demonstrate >100-fold selectivity for the structurally related aspartyl proteases cathepsin D, renin and pepsin. Alkyl and alkoxy groups at the meta-position of the P1 phenyl, which extend toward the S3 region of the enzyme, have contributed to the ligand's reduced affinity for the efflux transporter protein P-gp, and decreased topological polar surface area, thus resulting in enhanced brain permeability. A fluorine substitution at the para-position of the P1 phenyl has contributed to 100-fold decrease of CYP3A4 inhibition and enhancement of compound metabolic stability. The plasma and brain protein binding properties of these new analogs are affected by substitutions at the P1 phenyl moiety. Higher compound protein binding was observed in the brain than in the plasma. Two structurally diverse potent BACE1 inhibitors (84 and 89) reduced 30% plasma Aβ40 in the Tg2576 mice in vivo model at 30 mg/kg p.o..

Research paper thumbnail of Comparison of Several Molecular Docking Programs: Pose Prediction and Virtual Screening Accuracy

Journal of Chemical Information and Modeling, 2009

Molecular docking programs are widely used modeling tools for predicting ligand binding modes and... more Molecular docking programs are widely used modeling tools for predicting ligand binding modes and structure based virtual screening. In this study, six molecular docking programs (DOCK, FlexX, GLIDE, ICM, PhDOCK, and Surflex) were evaluated using metrics intended to assess docking pose and virtual screening accuracy. Cognate ligand docking to 68 diverse, high-resolution X-ray complexes revealed that ICM, GLIDE, and Surflex generated ligand poses close to the X-ray conformation more often than the other docking programs. GLIDE and Surflex also outperformed the other docking programs when used for virtual screening, based on mean ROC AUC and ROC enrichment values obtained for the 40 protein targets in the Directory of Useful Decoys (DUD). Further analysis uncovered general trends in accuracy that are specific for particular protein families. Modifying basic parameters in the software was shown to have a significant effect on docking and virtual screening results, suggesting that expert knowledge is critical for optimizing the accuracy of these methods.