Donna Ferguson - Academia.edu (original) (raw)

Papers by Donna Ferguson

Research paper thumbnail of Enhanced specificity of high sensitivity somatic variant profiling in cell-free DNA via paired normal sequencing: design, validation, and clinical experience of the MSK-ACCESS liquid biopsy assay

Circulating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate... more Circulating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate somatic tumor alterations non-invasively or when adequate tissue is unavailable. We have developed and clinically implemented MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), an NGS assay for detection of very low frequency somatic alterations in select exons and introns of 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 98% for a priori mutation profiling. To evaluate the performance and utility of MSK-ACCESS, we report results from the first 681 prospective blood samples (617 patients) that underwent clinical analysis to guide patient management. Somatic mutations, copy number, and/or structural variants were detected in 73% of the samples, and 56% of these circulating-tumor DNA (ctDNA) positive samples had clinically actionable alterations. The utilization of matched white blood cell seq...

Research paper thumbnail of HIV Protease Inhibitors Possessing a Novel, High-Affinity, and Achiral P1'/P2' Ligand with a Unique Pattern of in Vitro Resistance. Importance of a Conformationally-Restricted Template in the Design of Enzyme Inhibitors

Journal of the American Chemical Society, 1995

Achiral pyran-2-one analogs possessing a 3-S-(2-alkylphenyl) group were determined to be high-aff... more Achiral pyran-2-one analogs possessing a 3-S-(2-alkylphenyl) group were determined to be high-affinity inhibitors for human immunodeficiency virus (HIV) protease (PR). Crystallographic, modeling, and structureactivity studies led to the 3-S-(2-tert-butylphenyl) moiety as an apparent optimal group to access the Si/Sl' pockets of the enzyme. Further optimization led to an inhibitor, 3-[(2-tert-butylphenyl)sulfanyl]-4-hydroxy-6-(3-methylphenyl)pyran-2-one (14), possessing a K'i of 3 nM. An X-ray crystallographic structure of an inhibitor, 4-hydroxy-3-[(2isopropylphenyl)sulfanyl]-6-phenylpyran-2-one (8), bound to HIV PR showed that the 3-S-(2-isopropylphenyl) group occupied the P i and PI' pockets, while other crucial interactions were common to those found with other pyran-2one analogs. The high potency observed for this series may be due, in part, to the restrictions on the intramolecular collapsibility of these molecules in aqueous solution, leading to a highly favorable hydrophobic effect on binding. Herein we report a novel PiP1' achiral ligand which results in a tight-binding inhibitor that occupies only three pockets in the enzyme and exhibits a unique pattern of in vitro resistance.

Research paper thumbnail of Novel Series of Achiral, Low Molecular Weight, and Potent HIV-1 Protease Inhibitors

Journal of the American Chemical Society, 1994

... JVN Vara Prasad,'vt Kimberly S. Para... more ... JVN Vara Prasad,'vt Kimberly S. Para: Elizabeth A. Lunney: Daniel F. Ortwine: James B. Dunbar, Jr.,? Donna Ferguson,t Peter J. Tummino,t Donald Hupe,t Bradley D. Tait: John M. Domagala: Christine Humblet,? T. N. Bhat,! Beishan Liu,! Diego MA Guerin,gJ Eric T. Baldwin,! ...

Research paper thumbnail of Inhibitors of HIV Protease: Unique Non‐peptide Active Site Templates

Journal of Molecular Recognition, 1996

New templates were designed and prepared which straddle the active site of HIV-1 protease. These ... more New templates were designed and prepared which straddle the active site of HIV-1 protease. These templates were designed to be 'flexible scaffolds' upon which substituents could be appended to fill the pockets of HIV protease. The new templates prepared and analysed were 4-hydroxy-5H-furan-2-ones, 4-hydroxy-5,6-dihydropyrones, 3-hydroxy-cyclohex-2-enones, and 4-hydroxy-2(lH)-pyridinones, of which the 4-hydroxy-5,6-dihydropyrones were found to be the most potent inhibitors of HIV-1 protease.

Research paper thumbnail of Nonpeptidic Potent HIV-1 Protease Inhibitors: (4-Hydroxy-6-phenyl-2-oxo-2H-pyran-3-yl)thiomethanes That Span P1-P2' Subsites in a Unique Mode of Binding

Journal of Medicinal Chemistry, 1995

Using molecular modeling and the information derived from the X-ray crystal structure of HIV-1 pr... more Using molecular modeling and the information derived from the X-ray crystal structure of HIV-1 protease (HIV PR) complexed with the pyran-2-one 1, a series of (4-hydroxy-6-phenyl-2-oxo-W-pyran-3-yl)thiomethanes was designed and analyzed as novel, nonpeptidic inhibitors of HIV PR. Structure-activity studies led to the discovery of inhibitor 19 having (RS)-1-(cyclopentylthio)-3-methylbutyl functionalization at the C-3 position, which exhibited a K, of 33 nM. A X-ray crystallographic structure of 19 bound to HIV PR showed that structural water-301 (inhibitor-flap-bridging water) was displaced by the inhibitor. Interestingly, the enol moiety of the pyran-2-one formed a hydrogen bond directly with Asp125 and with Asp25 via a bridging water molecule, thus illustrating a unique mode of active site binding by a n HIV PR inhibitor. The pendant cyclopentyl and isobutyl groups of 19 occupied the SI' and SZ' binding sites, respectively, whereas the 6-phenyl group occupied a region in between the SI and SS pockets of HIV PR. Selected compounds were tested for antiviral activity on H9 cells infected with HIV-lIIIb. A correlation between enzymatic activity and antiviral activity was not found in this series. The best antiviral compound in this series, 18, contained (RS)-3-[cyclopentyl(cyclopentylthio)methyll functionalization at the C-3 position of the pyran-2-one ring and exhibited a C I C~O of 14 pM and TC50 of 70 pM. These studies demonstrate that potent enzyme inhibition can be achieved by inhibitors that span only three subsites.

Research paper thumbnail of A Novel Nonpeptide HIV-1 Protease Inhibitor: Elucidation of the Binding Mode and Its Application in the Design of Related Analogs

Journal of Medicinal Chemistry, 1994

HIV-1 protease has been identified as a significant target enzyme in AIDS research. While numerou... more HIV-1 protease has been identified as a significant target enzyme in AIDS research. While numerous peptide-derived inhibitors have been described, the identification of a nonpeptide inhibitor remains a n important goal. Using a n HN-1 protease mass screening technique, 4-hydroxy-3-(3-phenoxypropyl)-W-l-benzopyran-2-one (1) was identified as a nonpeptide competitive inhibitor of the enzyme. Employing a Monte Carlo-based docking procedure, the coumarin was docked in the active site of the enzyme, revealing a binding mode that was later confirmed by the X-ray crystal analysis. Several analogs were prepared to test the binding interactions and improve the overall binding affhity. The most active compound in the study was 4,7-dihydroxy-3-[4-(2-methoxyphenyl)buty1l-W-l-benzopyran-2-one (31).

Research paper thumbnail of 5,6-Dihydropyran-2-ones Possessing Various Sulfonyl Functionalities:  Potent Nonpeptidic Inhibitors of HIV Protease

Journal of Medicinal Chemistry, 2000

Research paper thumbnail of Synthesis of 5,6-Dihydro-4-hydroxy-2- pyrones as HIV-1 Protease Inhibitors:  The Profound Effect of Polarity on Antiviral Activity

Journal of Medicinal Chemistry, 1997

Research paper thumbnail of 6-Phenyl-6-alkylamido-5,6-dihydro-2H-pyran-2-ones: novel HIV protease inhibitors

Bioorganic & Medicinal Chemistry Letters, 1996

Publications from our laboratories have recently described a series of 3-thioaryl substituted-4-h... more Publications from our laboratories have recently described a series of 3-thioaryl substituted-4-hydroxy-pyrones1 as HIV protease inhibitors. The current work examines the analogous 5, 6-dihydro-2H-pyran-2-ones with 6, 6-substitutions focusing on the use of 1°, 2°, and 3° ...

Research paper thumbnail of A topliss tree analysis of the HIV-protease inhibitory activity of 6-phenyl-4-hydroxy-pyran-2-ones

Bioorganic & Medicinal Chemistry Letters, 1996

In a study of 4-hydroxy-pyran-2-ones as possible inhibitors of HIV protease, a series of compound... more In a study of 4-hydroxy-pyran-2-ones as possible inhibitors of HIV protease, a series of compounds were synthesized following the Topliss operational scheme for substitution on a phenyl group at the 6 position of the pyrone. In addition, a number of compounds with polar substituents ...

Research paper thumbnail of Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing a novel and achiral 3-(2-t-butyl-5-methyl-4-sulfamate)phenylthio moiety

Bioorganic & Medicinal Chemistry Letters, 1999

Dihydropyran-2-ones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were d... more Dihydropyran-2-ones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were designed to reach S 3' pocket of the HIV protease. Synthetic routes for the preparation of thiotosylates possessing 3-(2-t-butyl-5-methyl-4-sulfamate) phenylthio moiety were established. SAR of various sulfamate analogs including HIV protease binding affinities, antiviral activities and therapeutic indices will be described.

Research paper thumbnail of Discovery and optimization of nonpeptide HIV-1 protease inhibitors

Bioorganic & Medicinal Chemistry, 1996

Several small, achiral nonpeptide inhibitors of H1V-I protease with low micromolar activity were ... more Several small, achiral nonpeptide inhibitors of H1V-I protease with low micromolar activity were identified by mass screening of the Parke-Davis compound library. Two of the compounds, structurally similar, were both found to be competitive and reversible inhibitors [compound 1, 4-hydroxy-3-(3-phenoxypropyl)-l-benzopyran-2-one: K, = 1.0 p.M; compound 2, 4-hydroxy-6-phenyl-3-(phenylthio)-pyran-2-one: K~ = 1.1 ~tM]. These inhibitors were chosen as initial leads for optimization of in vitro inhibitory activity based on molecular modeling and X-ray crystallographic structural data. While improvements in inhibitory potency were small with analogues of compound 1, important X-ray crystallographic structural information of the enzyme-inhibitor complex was gained. When bound, 1 was found to displace H20301 in the active site while hydrogen bonding to the catalytic Asps and Ile50 and Ilel50. "[he pyranone group of compound 2 was found to bind at the active site in the same manner, with the 6-phenyl and the 3-phenylthio occupying P1 and PI', respectively. The structural information was used to develop design strategies to reach three or four of the internal pockets, P2-P2'. This work led to analogues of diverse structure with high potency (IC50 < 10 nM) that contain either one or no chiral centers and remain nonpeptidic. The highly potent compounds possess less anti-HIV activity in cellular assays than expected, and current optimization now focuses on increasing cellular activity. The value of the HIV-1 protease inhibitors described is their potential as better pharmacological agents with a different,pattern of viral resistance development, relative to the peptidic inhibitors in human clinical trials.

Research paper thumbnail of Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor

Bioorganic & Medicinal Chemistry, 1999

With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydro... more With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation.

Research paper thumbnail of Competitive Inhibition of HIV-1 Protease by Warfarin Derivatives

Biochemical and Biophysical Research Communications, 1994

The oral anticoagulant warfarin (4-hydroxy-3-(3-oxo-1-phenylbutyl)- benzopyran-2-one) is a struct... more The oral anticoagulant warfarin (4-hydroxy-3-(3-oxo-1-phenylbutyl)- benzopyran-2-one) is a structurally novel low micromolar competitive inhibitor of HIV-1 protease in vitro. It was recently reported that warfarin inhibits HIV-1 infection in U-1 monocytes and viral production in ACH-2 lymphocytes (Bourinbaiar, A.S. et al., (1993) AIDS 7, 129-130). Our results demonstrate that warfarin and a series of structurally related analogs inhibit the viral protease, the most potent analog having an IC50 = 1.9 microM. Kinetic analysis reveals inhibition by warfarin occurs in a competitive manner, with Ki = 3.3 microM. While it is unclear whether the cellular inhibition previously reported is due to inhibition of HIV-1 protease, the warfarin analogs are a novel class of nonpeptide HIV-1 protease inhibitors.

Research paper thumbnail of Nonpeptidic HIV Protease Inhibitors: 4-Hydroxy-pyran-2-one Inhibitors with Functional Tethers to P1Phenyl Ring to Reach S3Pocket of the Enzyme

Biochemical and Biophysical Research Communications, 1996

A systematic study of tethering various groups on 6-phenyl ring of 4-hydroxy-6-phenyl-3-[(2-isopr... more A systematic study of tethering various groups on 6-phenyl ring of 4-hydroxy-6-phenyl-3-[(2-isopropylphenyl)thio]pyran-2-one was performed to increase the binding affinity with HIV protease. This tethering approach was aimed to fill S3 pocket of the enzyme. Thus, tethering hydrophilic groups resulted in more potent inhibitors. Similarly, various aromatic hydrophobic rings as well as heterocyclic rings were explored as tethering substituents to alter the physical properties as well as to enhance the binding affinity with HIV protease. Inhibitor 24, 4-hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(3-pyridinylmethoxy+ ++ ) phenyl]-2H-pyran-2-one, was evaluated as a prototypic lead structure to study various physical as well as pharmacological properties of this class of HIV protease inhibitors.

Research paper thumbnail of 4-Hydroxy-5,6-Dihydro-2H-pyran-2-ones. 3. Bicyclic and hetero-aromatic ring systems as 3-position scaffolds to bind to S1′ and S2′ of the HIV-1 protease enzyme

Bioorganic & Medicinal Chemistry Letters, 1999

Research paper thumbnail of Enhanced specificity of high sensitivity somatic variant profiling in cell-free DNA via paired normal sequencing: design, validation, and clinical experience of the MSK-ACCESS liquid biopsy assay

Circulating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate... more Circulating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate somatic tumor alterations non-invasively or when adequate tissue is unavailable. We have developed and clinically implemented MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), an NGS assay for detection of very low frequency somatic alterations in select exons and introns of 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 98% for a priori mutation profiling. To evaluate the performance and utility of MSK-ACCESS, we report results from the first 681 prospective blood samples (617 patients) that underwent clinical analysis to guide patient management. Somatic mutations, copy number, and/or structural variants were detected in 73% of the samples, and 56% of these circulating-tumor DNA (ctDNA) positive samples had clinically actionable alterations. The utilization of matched white blood cell seq...

Research paper thumbnail of HIV Protease Inhibitors Possessing a Novel, High-Affinity, and Achiral P1'/P2' Ligand with a Unique Pattern of in Vitro Resistance. Importance of a Conformationally-Restricted Template in the Design of Enzyme Inhibitors

Journal of the American Chemical Society, 1995

Achiral pyran-2-one analogs possessing a 3-S-(2-alkylphenyl) group were determined to be high-aff... more Achiral pyran-2-one analogs possessing a 3-S-(2-alkylphenyl) group were determined to be high-affinity inhibitors for human immunodeficiency virus (HIV) protease (PR). Crystallographic, modeling, and structureactivity studies led to the 3-S-(2-tert-butylphenyl) moiety as an apparent optimal group to access the Si/Sl' pockets of the enzyme. Further optimization led to an inhibitor, 3-[(2-tert-butylphenyl)sulfanyl]-4-hydroxy-6-(3-methylphenyl)pyran-2-one (14), possessing a K'i of 3 nM. An X-ray crystallographic structure of an inhibitor, 4-hydroxy-3-[(2isopropylphenyl)sulfanyl]-6-phenylpyran-2-one (8), bound to HIV PR showed that the 3-S-(2-isopropylphenyl) group occupied the P i and PI' pockets, while other crucial interactions were common to those found with other pyran-2one analogs. The high potency observed for this series may be due, in part, to the restrictions on the intramolecular collapsibility of these molecules in aqueous solution, leading to a highly favorable hydrophobic effect on binding. Herein we report a novel PiP1' achiral ligand which results in a tight-binding inhibitor that occupies only three pockets in the enzyme and exhibits a unique pattern of in vitro resistance.

Research paper thumbnail of Novel Series of Achiral, Low Molecular Weight, and Potent HIV-1 Protease Inhibitors

Journal of the American Chemical Society, 1994

... JVN Vara Prasad,&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#x27;vt Kimberly S. Para... more ... JVN Vara Prasad,&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#x27;vt Kimberly S. Para: Elizabeth A. Lunney: Daniel F. Ortwine: James B. Dunbar, Jr.,? Donna Ferguson,t Peter J. Tummino,t Donald Hupe,t Bradley D. Tait: John M. Domagala: Christine Humblet,? T. N. Bhat,! Beishan Liu,! Diego MA Guerin,gJ Eric T. Baldwin,! ...

Research paper thumbnail of Inhibitors of HIV Protease: Unique Non‐peptide Active Site Templates

Journal of Molecular Recognition, 1996

New templates were designed and prepared which straddle the active site of HIV-1 protease. These ... more New templates were designed and prepared which straddle the active site of HIV-1 protease. These templates were designed to be 'flexible scaffolds' upon which substituents could be appended to fill the pockets of HIV protease. The new templates prepared and analysed were 4-hydroxy-5H-furan-2-ones, 4-hydroxy-5,6-dihydropyrones, 3-hydroxy-cyclohex-2-enones, and 4-hydroxy-2(lH)-pyridinones, of which the 4-hydroxy-5,6-dihydropyrones were found to be the most potent inhibitors of HIV-1 protease.

Research paper thumbnail of Nonpeptidic Potent HIV-1 Protease Inhibitors: (4-Hydroxy-6-phenyl-2-oxo-2H-pyran-3-yl)thiomethanes That Span P1-P2' Subsites in a Unique Mode of Binding

Journal of Medicinal Chemistry, 1995

Using molecular modeling and the information derived from the X-ray crystal structure of HIV-1 pr... more Using molecular modeling and the information derived from the X-ray crystal structure of HIV-1 protease (HIV PR) complexed with the pyran-2-one 1, a series of (4-hydroxy-6-phenyl-2-oxo-W-pyran-3-yl)thiomethanes was designed and analyzed as novel, nonpeptidic inhibitors of HIV PR. Structure-activity studies led to the discovery of inhibitor 19 having (RS)-1-(cyclopentylthio)-3-methylbutyl functionalization at the C-3 position, which exhibited a K, of 33 nM. A X-ray crystallographic structure of 19 bound to HIV PR showed that structural water-301 (inhibitor-flap-bridging water) was displaced by the inhibitor. Interestingly, the enol moiety of the pyran-2-one formed a hydrogen bond directly with Asp125 and with Asp25 via a bridging water molecule, thus illustrating a unique mode of active site binding by a n HIV PR inhibitor. The pendant cyclopentyl and isobutyl groups of 19 occupied the SI' and SZ' binding sites, respectively, whereas the 6-phenyl group occupied a region in between the SI and SS pockets of HIV PR. Selected compounds were tested for antiviral activity on H9 cells infected with HIV-lIIIb. A correlation between enzymatic activity and antiviral activity was not found in this series. The best antiviral compound in this series, 18, contained (RS)-3-[cyclopentyl(cyclopentylthio)methyll functionalization at the C-3 position of the pyran-2-one ring and exhibited a C I C~O of 14 pM and TC50 of 70 pM. These studies demonstrate that potent enzyme inhibition can be achieved by inhibitors that span only three subsites.

Research paper thumbnail of A Novel Nonpeptide HIV-1 Protease Inhibitor: Elucidation of the Binding Mode and Its Application in the Design of Related Analogs

Journal of Medicinal Chemistry, 1994

HIV-1 protease has been identified as a significant target enzyme in AIDS research. While numerou... more HIV-1 protease has been identified as a significant target enzyme in AIDS research. While numerous peptide-derived inhibitors have been described, the identification of a nonpeptide inhibitor remains a n important goal. Using a n HN-1 protease mass screening technique, 4-hydroxy-3-(3-phenoxypropyl)-W-l-benzopyran-2-one (1) was identified as a nonpeptide competitive inhibitor of the enzyme. Employing a Monte Carlo-based docking procedure, the coumarin was docked in the active site of the enzyme, revealing a binding mode that was later confirmed by the X-ray crystal analysis. Several analogs were prepared to test the binding interactions and improve the overall binding affhity. The most active compound in the study was 4,7-dihydroxy-3-[4-(2-methoxyphenyl)buty1l-W-l-benzopyran-2-one (31).

Research paper thumbnail of 5,6-Dihydropyran-2-ones Possessing Various Sulfonyl Functionalities:  Potent Nonpeptidic Inhibitors of HIV Protease

Journal of Medicinal Chemistry, 2000

Research paper thumbnail of Synthesis of 5,6-Dihydro-4-hydroxy-2- pyrones as HIV-1 Protease Inhibitors:  The Profound Effect of Polarity on Antiviral Activity

Journal of Medicinal Chemistry, 1997

Research paper thumbnail of 6-Phenyl-6-alkylamido-5,6-dihydro-2H-pyran-2-ones: novel HIV protease inhibitors

Bioorganic & Medicinal Chemistry Letters, 1996

Publications from our laboratories have recently described a series of 3-thioaryl substituted-4-h... more Publications from our laboratories have recently described a series of 3-thioaryl substituted-4-hydroxy-pyrones1 as HIV protease inhibitors. The current work examines the analogous 5, 6-dihydro-2H-pyran-2-ones with 6, 6-substitutions focusing on the use of 1°, 2°, and 3° ...

Research paper thumbnail of A topliss tree analysis of the HIV-protease inhibitory activity of 6-phenyl-4-hydroxy-pyran-2-ones

Bioorganic & Medicinal Chemistry Letters, 1996

In a study of 4-hydroxy-pyran-2-ones as possible inhibitors of HIV protease, a series of compound... more In a study of 4-hydroxy-pyran-2-ones as possible inhibitors of HIV protease, a series of compounds were synthesized following the Topliss operational scheme for substitution on a phenyl group at the 6 position of the pyrone. In addition, a number of compounds with polar substituents ...

Research paper thumbnail of Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing a novel and achiral 3-(2-t-butyl-5-methyl-4-sulfamate)phenylthio moiety

Bioorganic & Medicinal Chemistry Letters, 1999

Dihydropyran-2-ones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were d... more Dihydropyran-2-ones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were designed to reach S 3' pocket of the HIV protease. Synthetic routes for the preparation of thiotosylates possessing 3-(2-t-butyl-5-methyl-4-sulfamate) phenylthio moiety were established. SAR of various sulfamate analogs including HIV protease binding affinities, antiviral activities and therapeutic indices will be described.

Research paper thumbnail of Discovery and optimization of nonpeptide HIV-1 protease inhibitors

Bioorganic & Medicinal Chemistry, 1996

Several small, achiral nonpeptide inhibitors of H1V-I protease with low micromolar activity were ... more Several small, achiral nonpeptide inhibitors of H1V-I protease with low micromolar activity were identified by mass screening of the Parke-Davis compound library. Two of the compounds, structurally similar, were both found to be competitive and reversible inhibitors [compound 1, 4-hydroxy-3-(3-phenoxypropyl)-l-benzopyran-2-one: K, = 1.0 p.M; compound 2, 4-hydroxy-6-phenyl-3-(phenylthio)-pyran-2-one: K~ = 1.1 ~tM]. These inhibitors were chosen as initial leads for optimization of in vitro inhibitory activity based on molecular modeling and X-ray crystallographic structural data. While improvements in inhibitory potency were small with analogues of compound 1, important X-ray crystallographic structural information of the enzyme-inhibitor complex was gained. When bound, 1 was found to displace H20301 in the active site while hydrogen bonding to the catalytic Asps and Ile50 and Ilel50. "[he pyranone group of compound 2 was found to bind at the active site in the same manner, with the 6-phenyl and the 3-phenylthio occupying P1 and PI', respectively. The structural information was used to develop design strategies to reach three or four of the internal pockets, P2-P2'. This work led to analogues of diverse structure with high potency (IC50 < 10 nM) that contain either one or no chiral centers and remain nonpeptidic. The highly potent compounds possess less anti-HIV activity in cellular assays than expected, and current optimization now focuses on increasing cellular activity. The value of the HIV-1 protease inhibitors described is their potential as better pharmacological agents with a different,pattern of viral resistance development, relative to the peptidic inhibitors in human clinical trials.

Research paper thumbnail of Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor

Bioorganic & Medicinal Chemistry, 1999

With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydro... more With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation.

Research paper thumbnail of Competitive Inhibition of HIV-1 Protease by Warfarin Derivatives

Biochemical and Biophysical Research Communications, 1994

The oral anticoagulant warfarin (4-hydroxy-3-(3-oxo-1-phenylbutyl)- benzopyran-2-one) is a struct... more The oral anticoagulant warfarin (4-hydroxy-3-(3-oxo-1-phenylbutyl)- benzopyran-2-one) is a structurally novel low micromolar competitive inhibitor of HIV-1 protease in vitro. It was recently reported that warfarin inhibits HIV-1 infection in U-1 monocytes and viral production in ACH-2 lymphocytes (Bourinbaiar, A.S. et al., (1993) AIDS 7, 129-130). Our results demonstrate that warfarin and a series of structurally related analogs inhibit the viral protease, the most potent analog having an IC50 = 1.9 microM. Kinetic analysis reveals inhibition by warfarin occurs in a competitive manner, with Ki = 3.3 microM. While it is unclear whether the cellular inhibition previously reported is due to inhibition of HIV-1 protease, the warfarin analogs are a novel class of nonpeptide HIV-1 protease inhibitors.

Research paper thumbnail of Nonpeptidic HIV Protease Inhibitors: 4-Hydroxy-pyran-2-one Inhibitors with Functional Tethers to P1Phenyl Ring to Reach S3Pocket of the Enzyme

Biochemical and Biophysical Research Communications, 1996

A systematic study of tethering various groups on 6-phenyl ring of 4-hydroxy-6-phenyl-3-[(2-isopr... more A systematic study of tethering various groups on 6-phenyl ring of 4-hydroxy-6-phenyl-3-[(2-isopropylphenyl)thio]pyran-2-one was performed to increase the binding affinity with HIV protease. This tethering approach was aimed to fill S3 pocket of the enzyme. Thus, tethering hydrophilic groups resulted in more potent inhibitors. Similarly, various aromatic hydrophobic rings as well as heterocyclic rings were explored as tethering substituents to alter the physical properties as well as to enhance the binding affinity with HIV protease. Inhibitor 24, 4-hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(3-pyridinylmethoxy+ ++ ) phenyl]-2H-pyran-2-one, was evaluated as a prototypic lead structure to study various physical as well as pharmacological properties of this class of HIV protease inhibitors.

Research paper thumbnail of 4-Hydroxy-5,6-Dihydro-2H-pyran-2-ones. 3. Bicyclic and hetero-aromatic ring systems as 3-position scaffolds to bind to S1′ and S2′ of the HIV-1 protease enzyme

Bioorganic & Medicinal Chemistry Letters, 1999