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Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPAR? Selective Agonist.

ABSTRACT: BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) ? agonist, with an EC50 of 4 nM for human PPAR? and >1000-fold selectivity vs human PPAR? (EC50 = 4.5 ?M) and PPAR? (EC50 > 100 ?M) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

SUBMITTER: Shi Y

PROVIDER: S-EPMC4904259 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist.

Shi Yan Y Li Jun J Kennedy Lawrence J LJ Tao Shiwei S Hernández Andrés S AS Lai Zhi Z Chen Sean S Wong Henry H Zhu Juliang J Trehan Ashok A Lim Ngiap-Kie NK Zhang Huiping H Chen Bang-Chi BC Locke Kenneth T KT O'Malley Kevin M KM Zhang Litao L Srivastava Rai Ajit RA Miao Bowman B Meyers Daniel S DS Monshizadegan Hossain H Search Debra D Grimm Denise D Zhang Rongan R Harrity Thomas T Kunselman Lori K LK Cap Michael M Muckelbauer Jodi J Chang Chiehying C Krystek Stanley R SR Li Yi-Xin YX Hosagrahara Vinayak V Zhang Lisa L Kadiyala Pathanjali P Xu Carrie C Blanar Michael A MA Zahler Robert R Mukherjee Ranjan R Cheng Peter T W PT Tino Joseph A JA

ACS medicinal chemistry letters 20160404 6

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 μM) and PPARδ (EC50 > 100 μM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacolog ...[more]

PMID: 27326332

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Project description:The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM) and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM) and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat) and 0.29 micromolar (human)). BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM). BMS-933043 treatment i) improved 24 hour novel object recognition memory in mice (0.1-10 mg/kg, sc), ii) reversed MK-801-induced deficits in Y maze performance in mice (1-10 mg/kg, sc) and set shift performance in rats (1-10 mg/kg, po) and iii) reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1-3 mg/kg, po). BMS-933043 also improved auditory gating (0.56-3 mg/kg, sc) and mismatch negativity (0.03-3 mg/kg, sc) in rats treated with S(+)ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.

Dataset Information

Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPAR? Selective Agonist.

Publications

Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist.

Similar Datasets

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