Peter Meinke | Merck - Academia.edu (original) (raw)

Papers by Peter Meinke

Research paper thumbnail of Aryl-link-aryl substituted thiazolidine-dione and oxazolidine-dione as sodium channel blockers

Research paper thumbnail of Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2)

Bioorganic & Medicinal Chemistry Letters, 2008

We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Opt... more We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.

Research paper thumbnail of Nodulisporic acid side-Chain modifications: access to the 2″, 3″, 4″, and 6″ registers

Bioorganic & Medicinal Chemistry Letters, 2003

Efficient routes to access the 2&... more Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA permitted a one-carbon homologation to the 6" register. These efforts identified new analogues with significant flea activity and illustrated the biological significance of unsaturation at the…

Research paper thumbnail of Synthesis of side chain truncated 3"-aldehyde, 3"-carboxylic acid, and 1"-aldehyde from nodulisporic acid A

Organic letters, Jan 18, 2002

An efficient synthesis of the truncated 3"-aldehyde (3) from nodulisporic acid A (1) under m... more An efficient synthesis of the truncated 3"-aldehyde (3) from nodulisporic acid A (1) under mild conditions is described. Further oxidation of 3 to 3"-carboxylic acid (4) and its subsequent oxidative degradation produced 1"-aldehyde (5). These new derivatives are versatile intermediates for the preparation of new, side chain modified derivatives of nodulisporic acid A. [reaction: see text]

Research paper thumbnail of C1 to C4 side chain modified nodulisporic acid analogs

Research paper thumbnail of Ivermectin and Nodulisporic Acid Receptors in Drosophila melanogaster Contain Both γ-Aminobutyric Acid-Gated Rdl and Glutamate-Gated GluClα Chloride Channel Subunits

Biochemistry, 2002

35 S-labeled derivatives of the insecticides nodulisporic acid and ivermectin were synthesized an... more 35 S-labeled derivatives of the insecticides nodulisporic acid and ivermectin were synthesized and demonstrated to bind with high affinity to a population of receptors in Drosophila head membranes that were previously shown to be associated with a glutamate-gated chloride channel. Nodulisporic acid binding was modeled as binding to a single population of receptors. Ivermectin binding was composed of at least two kinetically distinct receptor populations, only one of which was associated with nodulisporic acid binding. The binding of these two ligands was modulated by glutamate, ivermectin, and antagonists of invertebrate γ-aminobutyric acid (GABA)ergic receptors. Because solubilized nodulisporic acid and ivermectin receptors comigrated as 230-kDa complexes by gel filtration, antisera specific for both the Drosophila glutamate-gated chloride channel subunit GluClR (DmGluClR) and the GABA-gated chloride channel subunit Rdl (DmRdl) proteins were generated and used to examine the possible coassembly of these two subunits within a single receptor complex. DmGluClR antibodies immunoprecipitated all of the ivermectin and nodulisporic acid receptors solubilized by detergent from Drosophila head membranes. DmRdl antibodies also immunoprecipitated all solubilized nodulisporic receptors, but only ∼70% of the ivermectin receptors. These data suggest that both DmGluClR and DmRdl are components of nodulisporic acid and ivermectin receptors, and that there also exists a distinct class of ivermectin receptors that contains the DmGluClR subunit but not the DmRdl subunit. This co-association of DmGluClR and DmRdl represents the first biochemical and immunological evidence of coassembly of subunits from two different subclasses of ligand-gated ion channel subunits.

Research paper thumbnail of Nodulisporic Acid Opens Insect Glutamate-Gated Chloride Channels: Identification of a New High Affinity Modulator

Research paper thumbnail of Discovery of potent and use-dependent sodium channel blockers for treatment of chronic pain

Bioorganic & Medicinal Chemistry Letters, 2005

A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pai... more A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pain is reported. Systematic structure-activity relationship studies, starting with compound 1, led to identification of potent analogs that displayed usedependent block of sodium channels, were efficacious in pain models in vivo, and most importantly, were devoid of activity against the cardiac potassium channel hERG.

Research paper thumbnail of A Disubstituted Succinamide Is a Potent Sodium Channel Blocker with Efficacy in a Rat Pain Model

Biochemistry, 2004

Sodium channel blockers are used clinically to treat a number of neuropathic pain conditions, but... more Sodium channel blockers are used clinically to treat a number of neuropathic pain conditions, but more potent and selective agents should improve on the therapeutic index of currently used drugs. In a high-throughput functional assay, a novel sodium channel (Na V ) blocker, N-{[2′-(aminosulfonyl)biphenyl-4-yl]methyl}-N′-(2,2′-bithien-5-ylmethyl)succinamide (BPBTS), was discovered. BPBTS is 2 orders of magnitude more potent than anticonvulsant and antiarrhythmic sodium channel blockers currently used to treat neuropathic pain. Resembling block by these agents, block of Na V 1.2, Na V 1.5, and Na V 1.7 by BPBTS was found to be voltage-and use-dependent. BPBTS appeared to bind preferentially to open and inactivated states and caused a dose-dependent hyperpolarizing shift in the steady-state availability curves for all sodium channel subtypes tested. The affinity of BPBTS for the resting and inactivated states of Na V 1.2 was 1.2 and 0.14 µM, respectively. BPBTS blocked Na V 1.7 and Na V 1.2 with similar potency, whereas block of Na V 1.5 was slightly more potent. The slow tetrodotoxin-resistant Na + current in smalldiameter DRG neurons was also potently blocked by BPBTS. [ 3 H]BPBTS bound with high affinity to a single class of sites present in rat brain synaptosomal membranes (K d ) 6.1 nM), and in membranes derived from HEK cells stably expressing Na V 1.5 (K d ) 0.9 nM). BPBTS dose-dependently attenuated nociceptive behavior in the formalin test, a rat model of tonic pain. On the basis of these findings, BPBTS represents a structurally novel and potent sodium channel blocker that may be used as a template for the development of analgesic agents.

Research paper thumbnail of Novel cyclopentane dicarboxamide sodium channel blockers as a potential treatment for chronic pain

Bioorganic & Medicinal Chemistry Letters, 2005

A series of new voltage-gated sodium channel blockers were prepared based on the screening lead s... more A series of new voltage-gated sodium channel blockers were prepared based on the screening lead succinic diamide BPBTS. Replacement of the succinimide linker with the more rigid cyclic 1,2-trans-diamide linker was well tolerated. N-Methylation on the biphenylsulfonamide side of the amide moiety significantly reduced the clearance rate in rat pharmacokinetic studies.

Research paper thumbnail of Structure activity relationship of substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-4)

Bioorganic & Medicinal Chemistry Letters, 2015

Bacterial resistance is rapidly growing, necessitating the need to discover new agents. Novel bac... more Bacterial resistance is rapidly growing, necessitating the need to discover new agents. Novel bacterial topoisomerase inhibitors (NBTIs) are new class of broad-spectrum antibacterial agents targeting bacterial DNA gyrase and topoisomerase IV. This class of inhibitors binds to an alternative binding site relative to fluoroquinolones and shows no cross-resistance to quinolones. NBTIs consist of three structural motifs. A structure activity relationship of the left hand motif 1,5-naphthyridine of oxabicyclooctane-linked NBTIs is described. Fifty five compounds were evaluated against a panel of key Gram-positive and Gram-negative strains of bacteria, as well as for hERG activity and five compounds were tested for in vivo efficacy in murine model of Staphylococcus aureus infection. These studies suggest that only a narrow range (activating and deactivating) of substitutions at C-2 and C-7 are tolerated for optimal antibacterial activity and spectrum. An alkoxy (methoxy) and CN at C-2, and a halogen and hydroxyl at C-7, appeared to be preferred in this series. Substitutions on the other three carbons generally have detrimental effect on the activity. No clear hERG activity SAR emerged from these substitutions.

Research paper thumbnail of Tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of left-hand-side moiety (Part-2)

Bioorganic & medicinal chemistry letters, Jan 24, 2015

Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibact... more Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1,5-naphthyridinone left hand side moieties have been described. Compounds with a (R)-hydroxy-1,5-naphthyridinone moiety (7) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25μg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound 7 showed intravenous and oral efficacy (ED50) at 3.2 and 27mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC50 >170μM). In general, lower logD attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding m...

Research paper thumbnail of Synthesis of 1,19-Aza-1,19-desoxy-avermectin B(1a): The First Avermectin Macrolactam

The Journal of organic chemistry, Jan 17, 1998

The first synthesis of 1,19-aza-1,19-desoxy-avermectin B(1a) (2) is described. This new macrolact... more The first synthesis of 1,19-aza-1,19-desoxy-avermectin B(1a) (2) is described. This new macrolactam, prepared efficiently from avermectin B(1a) (1a) in seven steps, was designed to form an intramolecular hydrogen bond between the amide carbonyl and the adjacent C7 tertiary hydroxyl via a six-center hydrogen bonding network. The presence of this intramolecular hydrogen bond is anticipated to confer additional conformational rigidity to the 16-membered macrocycle.

Research paper thumbnail of Nodulisporic acid side-Chain modifications: access to the 2″, 3″, 4″, and 6″ registers

Bioorganic & Medicinal Chemistry Letters, 2003

Efficient routes to access the 2&... more Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA permitted a one-carbon homologation to the…

Research paper thumbnail of Synthesis of Nodulisporic Acid 2''-Oxazoles and 2''-Thiazoles

Organic …, 2001

[reaction--see text] The semisynthetic conversion of nodulisporic acid A (1) into a set of three ... more [reaction--see text] The semisynthetic conversion of nodulisporic acid A (1) into a set of three heterocyclic side chain derivatives provided compounds, highlighted by 6, with an improved spectrum of ectoparasiticidal activity and pharmacokinetic profile relative to the natural product.

Research paper thumbnail of Design of potent and selective GPR119 agonists for type II diabetes

Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist ... more Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC 50 = 3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58).

Research paper thumbnail of Selective Small-Molecule Agonists of G Protein–coupled Receptor 40 Promote Glucose-Dependent Insulin Secretion and Reduce Blood Glucose In Mice

Diabetes, 2008

OBJECTIVE— Acute activation of G protein–coupled receptor 40 (GPR40) by free fatty acids (FFAs) o... more OBJECTIVE— Acute activation of G protein–coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 ...

Research paper thumbnail of Apicidin: a Novel Antiprotozoal Agent That Inhibits Parasite Histone Deacetylase

Proceedings of the …, 1996

A novel fungal metabolite, apicidin [cyclo(N-O-methyl-l-tryptophanyl-l-isoleucinyl-d-pipecolinyl ... more A novel fungal metabolite, apicidin [cyclo(N-O-methyl-l-tryptophanyl-l-isoleucinyl-d-pipecolinyl -l-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally ...

Research paper thumbnail of Oxabicyclooctane-Linked Novel Bacterial Topoisomerase Inhibitors as Broad Spectrum Antibacterial Agents

ACS Medicinal Chemistry Letters, 2014

Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the di... more Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC 50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC 50 = 1.02 μM) and topo IV (IC 50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED 50 ) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.

Research paper thumbnail of Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

ACS Medicinal Chemistry Letters, 2013

Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, th... more Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption.

Research paper thumbnail of Aryl-link-aryl substituted thiazolidine-dione and oxazolidine-dione as sodium channel blockers

Research paper thumbnail of Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2)

Bioorganic & Medicinal Chemistry Letters, 2008

We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Opt... more We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.

Research paper thumbnail of Nodulisporic acid side-Chain modifications: access to the 2″, 3″, 4″, and 6″ registers

Bioorganic & Medicinal Chemistry Letters, 2003

Efficient routes to access the 2&... more Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA permitted a one-carbon homologation to the 6" register. These efforts identified new analogues with significant flea activity and illustrated the biological significance of unsaturation at the…

Research paper thumbnail of Synthesis of side chain truncated 3"-aldehyde, 3"-carboxylic acid, and 1"-aldehyde from nodulisporic acid A

Organic letters, Jan 18, 2002

An efficient synthesis of the truncated 3"-aldehyde (3) from nodulisporic acid A (1) under m... more An efficient synthesis of the truncated 3"-aldehyde (3) from nodulisporic acid A (1) under mild conditions is described. Further oxidation of 3 to 3"-carboxylic acid (4) and its subsequent oxidative degradation produced 1"-aldehyde (5). These new derivatives are versatile intermediates for the preparation of new, side chain modified derivatives of nodulisporic acid A. [reaction: see text]

Research paper thumbnail of C1 to C4 side chain modified nodulisporic acid analogs

Research paper thumbnail of Ivermectin and Nodulisporic Acid Receptors in Drosophila melanogaster Contain Both γ-Aminobutyric Acid-Gated Rdl and Glutamate-Gated GluClα Chloride Channel Subunits

Biochemistry, 2002

35 S-labeled derivatives of the insecticides nodulisporic acid and ivermectin were synthesized an... more 35 S-labeled derivatives of the insecticides nodulisporic acid and ivermectin were synthesized and demonstrated to bind with high affinity to a population of receptors in Drosophila head membranes that were previously shown to be associated with a glutamate-gated chloride channel. Nodulisporic acid binding was modeled as binding to a single population of receptors. Ivermectin binding was composed of at least two kinetically distinct receptor populations, only one of which was associated with nodulisporic acid binding. The binding of these two ligands was modulated by glutamate, ivermectin, and antagonists of invertebrate γ-aminobutyric acid (GABA)ergic receptors. Because solubilized nodulisporic acid and ivermectin receptors comigrated as 230-kDa complexes by gel filtration, antisera specific for both the Drosophila glutamate-gated chloride channel subunit GluClR (DmGluClR) and the GABA-gated chloride channel subunit Rdl (DmRdl) proteins were generated and used to examine the possible coassembly of these two subunits within a single receptor complex. DmGluClR antibodies immunoprecipitated all of the ivermectin and nodulisporic acid receptors solubilized by detergent from Drosophila head membranes. DmRdl antibodies also immunoprecipitated all solubilized nodulisporic receptors, but only ∼70% of the ivermectin receptors. These data suggest that both DmGluClR and DmRdl are components of nodulisporic acid and ivermectin receptors, and that there also exists a distinct class of ivermectin receptors that contains the DmGluClR subunit but not the DmRdl subunit. This co-association of DmGluClR and DmRdl represents the first biochemical and immunological evidence of coassembly of subunits from two different subclasses of ligand-gated ion channel subunits.

Research paper thumbnail of Nodulisporic Acid Opens Insect Glutamate-Gated Chloride Channels: Identification of a New High Affinity Modulator

Research paper thumbnail of Discovery of potent and use-dependent sodium channel blockers for treatment of chronic pain

Bioorganic & Medicinal Chemistry Letters, 2005

A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pai... more A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pain is reported. Systematic structure-activity relationship studies, starting with compound 1, led to identification of potent analogs that displayed usedependent block of sodium channels, were efficacious in pain models in vivo, and most importantly, were devoid of activity against the cardiac potassium channel hERG.

Research paper thumbnail of A Disubstituted Succinamide Is a Potent Sodium Channel Blocker with Efficacy in a Rat Pain Model

Biochemistry, 2004

Sodium channel blockers are used clinically to treat a number of neuropathic pain conditions, but... more Sodium channel blockers are used clinically to treat a number of neuropathic pain conditions, but more potent and selective agents should improve on the therapeutic index of currently used drugs. In a high-throughput functional assay, a novel sodium channel (Na V ) blocker, N-{[2′-(aminosulfonyl)biphenyl-4-yl]methyl}-N′-(2,2′-bithien-5-ylmethyl)succinamide (BPBTS), was discovered. BPBTS is 2 orders of magnitude more potent than anticonvulsant and antiarrhythmic sodium channel blockers currently used to treat neuropathic pain. Resembling block by these agents, block of Na V 1.2, Na V 1.5, and Na V 1.7 by BPBTS was found to be voltage-and use-dependent. BPBTS appeared to bind preferentially to open and inactivated states and caused a dose-dependent hyperpolarizing shift in the steady-state availability curves for all sodium channel subtypes tested. The affinity of BPBTS for the resting and inactivated states of Na V 1.2 was 1.2 and 0.14 µM, respectively. BPBTS blocked Na V 1.7 and Na V 1.2 with similar potency, whereas block of Na V 1.5 was slightly more potent. The slow tetrodotoxin-resistant Na + current in smalldiameter DRG neurons was also potently blocked by BPBTS. [ 3 H]BPBTS bound with high affinity to a single class of sites present in rat brain synaptosomal membranes (K d ) 6.1 nM), and in membranes derived from HEK cells stably expressing Na V 1.5 (K d ) 0.9 nM). BPBTS dose-dependently attenuated nociceptive behavior in the formalin test, a rat model of tonic pain. On the basis of these findings, BPBTS represents a structurally novel and potent sodium channel blocker that may be used as a template for the development of analgesic agents.

Research paper thumbnail of Novel cyclopentane dicarboxamide sodium channel blockers as a potential treatment for chronic pain

Bioorganic & Medicinal Chemistry Letters, 2005

A series of new voltage-gated sodium channel blockers were prepared based on the screening lead s... more A series of new voltage-gated sodium channel blockers were prepared based on the screening lead succinic diamide BPBTS. Replacement of the succinimide linker with the more rigid cyclic 1,2-trans-diamide linker was well tolerated. N-Methylation on the biphenylsulfonamide side of the amide moiety significantly reduced the clearance rate in rat pharmacokinetic studies.

Research paper thumbnail of Structure activity relationship of substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-4)

Bioorganic & Medicinal Chemistry Letters, 2015

Bacterial resistance is rapidly growing, necessitating the need to discover new agents. Novel bac... more Bacterial resistance is rapidly growing, necessitating the need to discover new agents. Novel bacterial topoisomerase inhibitors (NBTIs) are new class of broad-spectrum antibacterial agents targeting bacterial DNA gyrase and topoisomerase IV. This class of inhibitors binds to an alternative binding site relative to fluoroquinolones and shows no cross-resistance to quinolones. NBTIs consist of three structural motifs. A structure activity relationship of the left hand motif 1,5-naphthyridine of oxabicyclooctane-linked NBTIs is described. Fifty five compounds were evaluated against a panel of key Gram-positive and Gram-negative strains of bacteria, as well as for hERG activity and five compounds were tested for in vivo efficacy in murine model of Staphylococcus aureus infection. These studies suggest that only a narrow range (activating and deactivating) of substitutions at C-2 and C-7 are tolerated for optimal antibacterial activity and spectrum. An alkoxy (methoxy) and CN at C-2, and a halogen and hydroxyl at C-7, appeared to be preferred in this series. Substitutions on the other three carbons generally have detrimental effect on the activity. No clear hERG activity SAR emerged from these substitutions.

Research paper thumbnail of Tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of left-hand-side moiety (Part-2)

Bioorganic & medicinal chemistry letters, Jan 24, 2015

Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibact... more Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1,5-naphthyridinone left hand side moieties have been described. Compounds with a (R)-hydroxy-1,5-naphthyridinone moiety (7) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25μg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound 7 showed intravenous and oral efficacy (ED50) at 3.2 and 27mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC50 >170μM). In general, lower logD attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding m...

Research paper thumbnail of Synthesis of 1,19-Aza-1,19-desoxy-avermectin B(1a): The First Avermectin Macrolactam

The Journal of organic chemistry, Jan 17, 1998

The first synthesis of 1,19-aza-1,19-desoxy-avermectin B(1a) (2) is described. This new macrolact... more The first synthesis of 1,19-aza-1,19-desoxy-avermectin B(1a) (2) is described. This new macrolactam, prepared efficiently from avermectin B(1a) (1a) in seven steps, was designed to form an intramolecular hydrogen bond between the amide carbonyl and the adjacent C7 tertiary hydroxyl via a six-center hydrogen bonding network. The presence of this intramolecular hydrogen bond is anticipated to confer additional conformational rigidity to the 16-membered macrocycle.

Research paper thumbnail of Nodulisporic acid side-Chain modifications: access to the 2″, 3″, 4″, and 6″ registers

Bioorganic & Medicinal Chemistry Letters, 2003

Efficient routes to access the 2&... more Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA permitted a one-carbon homologation to the…

Research paper thumbnail of Synthesis of Nodulisporic Acid 2''-Oxazoles and 2''-Thiazoles

Organic …, 2001

[reaction--see text] The semisynthetic conversion of nodulisporic acid A (1) into a set of three ... more [reaction--see text] The semisynthetic conversion of nodulisporic acid A (1) into a set of three heterocyclic side chain derivatives provided compounds, highlighted by 6, with an improved spectrum of ectoparasiticidal activity and pharmacokinetic profile relative to the natural product.

Research paper thumbnail of Design of potent and selective GPR119 agonists for type II diabetes

Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist ... more Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC 50 = 3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58).

Research paper thumbnail of Selective Small-Molecule Agonists of G Protein–coupled Receptor 40 Promote Glucose-Dependent Insulin Secretion and Reduce Blood Glucose In Mice

Diabetes, 2008

OBJECTIVE— Acute activation of G protein–coupled receptor 40 (GPR40) by free fatty acids (FFAs) o... more OBJECTIVE— Acute activation of G protein–coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 ...

Research paper thumbnail of Apicidin: a Novel Antiprotozoal Agent That Inhibits Parasite Histone Deacetylase

Proceedings of the …, 1996

A novel fungal metabolite, apicidin [cyclo(N-O-methyl-l-tryptophanyl-l-isoleucinyl-d-pipecolinyl ... more A novel fungal metabolite, apicidin [cyclo(N-O-methyl-l-tryptophanyl-l-isoleucinyl-d-pipecolinyl -l-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally ...

Research paper thumbnail of Oxabicyclooctane-Linked Novel Bacterial Topoisomerase Inhibitors as Broad Spectrum Antibacterial Agents

ACS Medicinal Chemistry Letters, 2014

Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the di... more Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC 50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC 50 = 1.02 μM) and topo IV (IC 50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED 50 ) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.

Research paper thumbnail of Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

ACS Medicinal Chemistry Letters, 2013

Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, th... more Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption.