Publications by authors named "Peter J Manley"

14 Publications

  • Page 1 of 1

Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics.

Bioorg Med Chem Lett 2017 02 16;27(4):1062-1069. Epub 2017 Jan 16.

Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.

Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, I, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current I, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for I over I (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans.
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http://dx.doi.org/10.1016/j.bmcl.2016.12.054DOI Listing
February 2017

Prediction of Metabolic Clearance for Low-Turnover Compounds Using Plated Hepatocytes with Enzyme Activity Correction.

Eur J Drug Metab Pharmacokinet 2017 Apr;42(2):319-326

Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, West Point, PA, 19486, USA.

Background And Objectives: Prediction of metabolic clearance has been a challenge for compounds exhibiting minimal turnover in typical in vitro stability experiments. The aim of the current study is to evaluate the utilization of plated human hepatocytes to predict intrinsic clearance of low-turnover compounds.

Methods: The disappearance of test compounds was determined for up to 48 h while enzyme activities in plated hepatocytes were monitored concurrently in a complimentary experiment.

Results: Consistent with literature reports, marked time-dependent loss of cytochrome P450 (CYP) enzyme activities was observed during the 48-h incubation period. To account for the loss of enzyme activities, a term "fraction of activity remaining" was calculated based on area-under-the-curve derived from the average rate of activity loss (k ), and then applied as a correction factor for intrinsic clearance determination. Twelve compounds were selected in this study to cover phase I and phase II biotransformation pathways, with in vivo intrinsic clearance values, representing metabolic clearance only, ranging from 0.66 to 47 ml/min/kg. Determination of in vitro intrinsic clearance using three individual preparations of hepatocytes revealed a reasonably good agreement (generally within threefold) between the predicted and the observed metabolic clearance for all 12 compounds tested.

Conclusions: The current results indicated that plated hepatocytes can be utilized to provide clearance predictions for compounds with low-turnover in humans when corrected for the loss in enzyme activities.
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http://dx.doi.org/10.1007/s13318-016-0336-3DOI Listing
April 2017

Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.

J Med Chem 2014 Jul 19;57(13):5800-16. Epub 2014 Jun 19.

Departments of Medicinal Chemistry, Biological Chemistry, Pain & Migraine, Molecular Systems, and Structural Biology, Merck Research Laboratories , P.O. Box 4, West Point, Pennsylvania 19486, United States.

We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.
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http://dx.doi.org/10.1021/jm5006429DOI Listing
July 2014

Characterization of non-nitrocatechol pan and isoform specific catechol-O-methyltransferase inhibitors and substrates.

ACS Chem Neurosci 2012 Feb 14;3(2):129-40. Epub 2011 Nov 14.

Psychiatric Research, Merck Sharp & Dohme Corp., West Point, Pennsylvania, USA.

Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since membrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial membrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity.
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http://dx.doi.org/10.1021/cn200109wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369789PMC
February 2012

Decahydroquinoline amides as highly selective CB2 agonists: role of selectivity on in vivo efficacy in a rodent model of analgesia.

Bioorg Med Chem Lett 2011 Apr 26;21(8):2359-64. Epub 2011 Feb 26.

Department of Medicinal Chemistry, Merck Research Laboratories, West Point PA, United States.

A novel series of decahydroquinoline CB2 agonists is described. Optimization of the amide substituent led to improvements in CB2/CB1 selectivity as well as physical properties. Two key compounds were examined in the rat CFA model of acute inflammatory pain. A moderately selective CB2 agonist was active in this model. A CB2 agonist lacking functional CB1 activity was inactive in this model despite high in vivo exposure both peripherally and centrally.
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http://dx.doi.org/10.1016/j.bmcl.2011.02.078DOI Listing
April 2011

Tricyclic imidazole antagonists of the Neuropeptide S Receptor.

Bioorg Med Chem Lett 2010 Aug 13;20(15):4704-8. Epub 2010 Apr 13.

Department of Medicinal Chemistry, Merck Research Laboratories, Boston, MA, USA.

A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.016DOI Listing
August 2010

Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model.

Bioorg Med Chem Lett 2008 Jun 1;18(11):3178-82. Epub 2008 May 1.

Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486 USA.

A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecule in particular, compound 17, has potent inhibitory activity against Akt1 and 2 in vivo in a mouse lung and efficacy in a tumor xenograft model.
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http://dx.doi.org/10.1016/j.bmcl.2008.04.074DOI Listing
June 2008

Potent N-(1,3-thiazol-2-yl)pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel.

J Med Chem 2004 Dec;47(25):6363-72

Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA.

A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.
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http://dx.doi.org/10.1021/jm049697fDOI Listing
December 2004

A new synthesis of naphthyridinones and quinolinones: palladium-catalyzed amidation of o-carbonyl-substituted aryl halides.

Org Lett 2004 Jul;6(14):2433-5

Department of Medicinal Chemistry, Merck and Co., Inc., P.O. Box 4, West Point, Pennsylvania 19486, USA.

[reaction: see text] An alternative to the Friedlander condensation for the synthesis of naphthyridinones and quinolinones has been discovered. Palladium-catalyzed amidation of halo aromatics substituted in the ortho position by a carbonyl functional group or its equivalent with primary or secondary amides leads to the formation of substituted naphthyridinones and quinolinones.
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http://dx.doi.org/10.1021/ol049165tDOI Listing
July 2004

2,4-disubstituted pyrimidines: a novel class of KDR kinase inhibitors.

Bioorg Med Chem Lett 2003 May;13(10):1673-7

Departments of Medicinal Chemistry and Cancer Research, Merck Research Laboratories, 19486, West Point, PA, USA

2,4-Disubstituted pyrimidines were synthesized as a novel class of KDR kinase inhibitors. Evaluation of the SAR of the screening lead compound 1 (KDR IC(50)=105 nM, Cell IC(50)=8% inhibition at 500 nM) led to the potent 3,5-dimethylaniline derivative 2d (KDR IC(50)=6 nM, cell IC(50)=19 nM).
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http://dx.doi.org/10.1016/s0960-894x(03)00244-0DOI Listing
May 2003

Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK.

J Med Chem 2003 Apr;46(9):1627-35

GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, P.O. Box 5089, Collegeville, Pennsylvania 19426, USA.

Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration. Through iterative medicinal chemistry aided by X-ray crystal structure analysis, a new series of inhibitors has been developed with greatly increased potency against FabI-containing organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compound 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compounds 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compounds to include the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.
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http://dx.doi.org/10.1021/jm0204035DOI Listing
April 2003

Phenylbutyrates as potent, orally bioavailable vitronectin receptor (integrin alphavbeta3) antagonists.

Bioorg Med Chem Lett 2003 Apr;13(8):1483-6

GlaxoSmithKline Pharmaceuticals, 1250 S. Collegeville Rd., PO Box 5089, PA 19426, USA.

In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.
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http://dx.doi.org/10.1016/s0960-894x(03)00102-1DOI Listing
April 2003

Discovery of a novel and potent class of FabI-directed antibacterial agents.

Antimicrob Agents Chemother 2002 10;46(10):3118-24

Microbial, Musculoskeletal and Proliferative Diseases Center of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA.

Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC128775PMC
http://dx.doi.org/10.1128/aac.46.10.3118-3124.2002DOI Listing
October 2002

A mild method for the formation and in situ reaction of imidoyl chlorides: conversion of pyridine-1-oxides to 2-aminopyridine amides.

Org Lett 2002 Sep;4(18):3127-9

Department of Medicinal Chemistry, Merck & Co., Inc., P.O. Box 4, West Point, Pennsylvania 19486, USA.

[reaction: see text] A mild, practical, one-pot method for the generation of imidoyl chlorides and their subsequent in situ reaction with pyridine-1-oxides is described. The imidoyl chlorides were formed from the reaction of secondary amides with a stoichiometric amount of oxalyl chloride and 2,6-lutidine in CH(2)Cl(2) at 0 degrees C. Upon warming of the reaction mixture to room temperature in the presence of pyridine-1-oxides, a rapid conversion to 2-aminopyridine amides was observed in moderate to excellent isolated yields.
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http://dx.doi.org/10.1021/ol0264556DOI Listing
September 2002