Research Parkway

Wallingford, CT, United States

Research Parkway

Wallingford, CT, United States
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Fernandes A.,Research Parkway | Wojcik T.,Research Parkway | Baireddy P.,Research Parkway | Pieschl R.,Research Parkway | And 5 more authors.
European Journal of Pharmacology | Year: 2015

N-methyl-d-aspartate (NMDA) receptor antagonists, including open channel blockers and GluN2B receptor subtype selective antagonists, have been developed for the treatment of depression. The current study investigated effects of systemically administered NMDA channel blockers and GluN2B receptor antagonists on NMDA receptor activity in rodents using in vivo [3H]MK-801 binding. The receptor occupancy of GluN2B antagonists was measured using ex vivo [3H]Ro 25-6981 binding. Ketamine, a NMDA receptor channel blocker, produced a dose/exposure- and time-dependent inhibition of in vivo [3H]MK-801 binding that was maximal at ~100%. The complete inhibition of in vivo [3H]MK-801 binding was also observed with NMDA receptor channel blockers, AZD6765 (Lanicemine) and MK-801 (Dizocilpine). CP-101,606 (Traxoprodil), a GluN2B antagonist, produced a dose/exposure- and time-dependent inhibition of in vivo [3H]MK-801 binding that was maximal at ~60%. Partial inhibition was also observed with other GluN2B antagonists including MK-0657 (CERC-301), EVT-101, Ro 25-6981 and radiprodil. For all GluN2B antagonists tested, partial [3H]MK-801 binding inhibition was achieved at doses saturating GluN2B receptor occupancy. Combined treatment with ketamine (10 mg/kg, i.p.) and Ro 25-6981(10 mg/kg, i.p.) produced a level of inhibition of in vivo [3H]MK-801 binding that was similar to treatment with either agent alone. In conclusion, this in vivo [3H]MK-801 binding study shows that NMDA receptor activity in the rodent forebrain can be inhibited completely by channel blockers, but only partially (~60%) by GluN2B receptor antagonists. At doses effective in preclinical models of depression, ketamine may preferentially inhibit the same population of NMDA receptors as Ro 25-6981, namely those containing the GluN2B subunit. © 2015 Elsevier B.V.


Romine J.L.,Bristol Myers Squibb | St. Laurent D.R.,Bristol Myers Squibb | Leet J.E.,Bristol Myers Squibb | Martin S.W.,Bristol Myers Squibb | And 13 more authors.
ACS Medicinal Chemistry Letters | Year: 2011

The iminothiazolidinone BMS-858 (2) was identified as a specific inhibitor of HCV replication in a genotype 1b replicon assay via a high-throughput screening campaign. A more potent analogue, BMS-824 (18), was used in resistance mapping studies, which revealed that inhibitory activity was related to disrupting the function of the HCV nonstructural protein 5A. Despite the development of coherent and interpretable SAR, it was subsequently discovered that in DMSO 18 underwent an oxidation and structural rearrangement to afford the thiohydantoin 47, a compound with reduced HCV inhibitory activity. However, HPLC bioassay fractionation studies performed after incubation of 18 in assay media led to the identification of fractions containing a dimeric species 48 that exhibited potent antiviral activity. Excision of the key elements hypothesized to be responsible for antiviral activity based on SAR observations reduced 48 to a simplified, symmetrical, pharmacophore realized most effectively with the stilbene 55, a compound that demonstrated potent inhibition of HCV in a genotype 1b replicon with an EC50 = 86 pM. © 2011 American Chemical Society.


Burrell R.C.,Research Parkway | Cao K.,Route 206 and Province Line Road | Bonacorsi Jr. S.J.,Route 206 and Province Line Road | Balasubramanian B.,Bristol Myers Squibb
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2010

A dual carbon-14 labeled peroxisome proliferator activated receptor α and γ (PPAR α and γ) dual agonist ([14C]-1) was synthesized for use in a human ADME study. A total of 9.5 mCi of [ 14C]-1 was prepared with a specific activity of 10.18 μCi/mg and a radiochemical purity of 99.85%. The title compound [14C]-1 was synthesized in 6 radioactive steps and a 23% radiochemical yield from the dual carbon-14 labeled intermediate [14C]-6. The dual carbon-14 labeled intermediate [14C]-6 was prepared by mixing equal millicurie amounts of mono labeled [14C]-6 Label A and mono labeled [14C]-6 Label B. Label A ([14C]-6 Label A) was prepared in 4 radioactive steps in a 55% yield from carbon-14 labeled potassium cyanide. Label B ([ 14C]-6 Label B) was prepared in 1 radioactive step in a 96% yield from carbon-14 labeled 4-hydroxyacetophenone. Copyright © 2010 John Wiley & Sons, Ltd.


Belema M.,Research Parkway | Nguyen V.N.,Research Parkway | Bachand C.,Research Parkway | Deon D.H.,Research Parkway | And 28 more authors.
Journal of Medicinal Chemistry | Year: 2014

The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan. © 2014 American Chemical Society.


Kubben N.,U.S. National Institutes of Health | Brimacombe K.R.,U.S. National Institutes of Health | Donegan M.,U.S. National Institutes of Health | Li Z.,U.S. National Institutes of Health | And 2 more authors.
Methods | Year: 2016

Hutchinson-Gilford Progeria Syndrome (HGPS) is an early onset lethal premature aging disorder caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A. The presence of progerin causes extensive morphological, epigenetic and DNA damage related nuclear defects that ultimately disrupt tissue and organismal functions. Hypothesis-driven approaches focused on HGPS affected pathways have been used in attempts to identify druggable targets with anti-progeroid effects. Here, we report an unbiased discovery approach to HGPS by implementation of a high-throughput, high-content imaging based screening method that enables systematic identification of small molecules that prevent the formation of multiple progerin-induced aging defects. Screening a library of 2816 FDA approved drugs, we identified retinoids as a novel class of compounds that reverses aging defects in HGPS patient skin fibroblasts. These findings establish a novel approach to anti-progeroid drug discovery. © 2016.


Belema M.,Research Parkway | Lopez O.D.,Research Parkway | Bender J.A.,Research Parkway | Romine J.L.,Research Parkway | And 8 more authors.
Journal of Medicinal Chemistry | Year: 2014

Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogues that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clinical trials with HCV NS5A RCIs. © 2014 American Chemical Society.


Goswami A.,Bristol Myers Squibb | Guo Z.,Bristol Myers Squibb | Tully T.P.,Bristol Myers Squibb | Rinaldi F.A.,Bristol Myers Squibb | And 5 more authors.
Journal of Molecular Catalysis B: Enzymatic | Year: 2015

Enzymatic transformation of betulinic acid by growing cells of microorganisms provided several hydroxylated and oxidized products. Bacillus megaterium SC16644 gave 7β,15α-dihydroxybetulinic acid, 7β,15α-dihydroxybetulonic acid, and a new compound 7β,15α,23-trihydroxybetulinic acid [3β,7β,15α,23-tetrahydroxy-lup-20(29)en-28-oic acid]. Another strain of B. megaterium SC6394 produced 30-oxobetulonic acid, and a mixture of 30-hydroxybetulonic acid and a new compound 7β-hydroxy-30-oxobetulonic acid [7β-hydroxy-3,30-dioxo-lup-20(29)en-28-oic acid]. Three products were obtained from the biotransformation of betulinic acid by Streptomyces fragilis SC16401: 7β-hydroxybetulonic acid, and two new compounds 2α,7β-dihydroxybetulinic acid [2α,3β,7β-trihydroxy-lup-20(29)en-28-oic acid] and 2-oxo-7β-hydroxy-betulinic acid [2-oxo-3β,7β-dihydroxy-lup-20(29)en-28-oic acid]. Cunninghamella elegans SC16025 gave 25-hydroxybetulinic acid from betulinic acid. Oxidation of betulinic acid by Aspergillus terreus SC16513 led to two A-ring fission products: 4-hydroxy-3,4-seco-lup-20(29)-en-3,28-dioic acid and 3,4-seco-lup-20(29), 4(23)-dien-3,28-dioic acid. B. megaterium SC16644 catalyzed transformation of betulonic acid provided 7β-hydroxybetulonic acid, 7β,15α-dihydroxybetulonic acid, and a new compound 7β,15α,30-trihydroxybetulonic acid [3-oxo-7β,15α,30-trihydroxy-lup-20(29)en-28-oic acid]. © 2015 Elsevier B.V. All rights reserved.


PubMed | Bristol Myers Squibb and Research Parkway
Type: | Journal: European journal of pharmacology | Year: 2015

N-methyl-D-aspartate (NMDA) receptor antagonists, including open channel blockers and GluN2B receptor subtype selective antagonists, have been developed for the treatment of depression. The current study investigated effects of systemically administered NMDA channel blockers and GluN2B receptor antagonists on NMDA receptor activity in rodents using in vivo [(3)H]MK-801 binding. The receptor occupancy of GluN2B antagonists was measured using ex vivo [(3)H]Ro 25-6981 binding. Ketamine, a NMDA receptor channel blocker, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~100%. The complete inhibition of in vivo [(3)H]MK-801 binding was also observed with NMDA receptor channel blockers, AZD6765 (Lanicemine) and MK-801 (Dizocilpine). CP-101,606 (Traxoprodil), a GluN2B antagonist, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~60%. Partial inhibition was also observed with other GluN2B antagonists including MK-0657 (CERC-301), EVT-101, Ro 25-6981 and radiprodil. For all GluN2B antagonists tested, partial [(3)H]MK-801 binding inhibition was achieved at doses saturating GluN2B receptor occupancy. Combined treatment with ketamine (10mg/kg, i.p.) and Ro 25-6981(10mg/kg, i.p.) produced a level of inhibition of in vivo [(3)H]MK-801 binding that was similar to treatment with either agent alone. In conclusion, this in vivo [(3)H]MK-801 binding study shows that NMDA receptor activity in the rodent forebrain can be inhibited completely by channel blockers, but only partially (~60%) by GluN2B receptor antagonists. At doses effective in preclinical models of depression, ketamine may preferentially inhibit the same population of NMDA receptors as Ro 25-6981, namely those containing the GluN2B subunit.


PubMed | Discovery Biology, Pharmaceutical Candidate Optimization and Research Parkway
Type: Journal Article | Journal: Drug discovery today. Technologies | Year: 2014

Drug discovery and development faces a growing challenge to improve the success rate of drug candidates and to accelerate the lengthy, expensive process of bringing new medicines to patients. The emerging methodology of biomarker models has the potential to assist in exploring and finding novel drug targets and to aid at an early stage by assessing efficacy, and addressing issues with metabolism, toxicity and pharmacokinetics. Biomarker discovery and monitoring assays depend on sophisticated analytical techniques such as mass spectrometry that provides the sensitivity and specificity required to establish the models.:

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