Discovery of trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as potent, orally bioavailable TGR5 (GPBAR1) agonists: Structure-activity relationships, lead optimization, and chronic in vivo efficacy

Journal of Medicinal Chemistry

Volumn 57, Issue 8, 2014, Pages 3263-3282

  Phillips, Dean P ^a   Gao, Wenqi ^a   Yang, Yang ^a   Zhang, Guobao ^a   Lerario, Isabelle K ^a   Lau, Thomas L ^a   Jiang, Jiqing ^a   Wang, Xia ^a   Nguyen, Deborah G ^a   Bhat, B Ganesh ^a   Trotter, Carol ^a   Sullivan, Heather ^a   Welzel, Gustav ^a   Landry, Jannine ^a   Chen, Yali ^a   Joseph, Sean B ^a   Li, Chun ^a   Gordon, W Perry ^a   Richmond, Wendy ^a   Johnson, Kevin ^a   Bretz, Angela ^a   Bursulaya, Badry ^a   Pan, Shifeng ^a   McNamara, Peter ^a   Seidel, H Martin ^b   more..

^a GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION   (United States)

^b Departments of Drug Discovery Biology Genomics Institute of the Novartis Research Foundation ^*

Author keywords

[No Author keywords available]

Indexed keywords

1 (4 METHYLPYRIMIDIN 2 YL) N PHENETHYLPIPERIDINE 3 CARBOXAMIDE; 1 [6 CHLORO 2 (FLUOROMETHYL)PYRIMIDIN 4 YL] N (4 CYANOPHENETHYL)PIPERIDINE 3 CARBOXAMIDE; 2,5 DIOXOPYRROLIDIN 1 YL 1 (4 METHYLPYRIMIDIN 2 YL)PIPERIDINE 3 CARBOXYLATE; G PROTEIN BILE ACID RECEPTOR 1; G PROTEIN COUPLED RECEPTOR; N (4 BROMOPHENETHYL) 1 (4 METHYLPYRIMIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CHLOROPHENETHYL) 1 (2 METHYLPYRIMIDIN 4 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CHLOROPHENETHYL) 1 (4 METHYLPYRIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CHLOROPHENETHYL) 1 (4 METHYLPYRIMIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CHLOROPHENETHYL) 1 (5 FLUORO 4 METHYLPYRIMIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CHLOROPHENETHYL) 1 (5 FLUOROPYRIMIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CHLOROPHENETHYL) 1 (6 METHYLPYRIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CHLOROPHENETHYL) 1 (PYRIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CHLOROPHENETHYL) 1 (PYRIMIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CHLOROPHENETHYL) 1 (PYRIMIDIN 4 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CYANOPHENETHYL) 1 (5 FLUORO 4 METHYLPYRIMIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CYANOPHENETHYL) 1 [2 (TRIFLUOROMETHYL)PYRIMIDIN 4 YL]PIPERIDINE 3 CARBOXAMIDE; N (4 CYANOPHENETHYL) 1 [2 METHYL 6 (4 METHYLPIPERAZIN 1 YL)PYRIMIDIN 4 YL]PIPERIDINE 3 CARBOXAMIDE; N (4 CYANOPHENETHYL) 1 [4 (4 METHYLPIPERAZIN 1 YL) 6 (TRIFLUOROMETHYL)PYRIMIDIN 2 YL]PIPERIDINE 3 CARBOXAMIDE; N (4 CYANOPHENETHYL) 1 [4 (TRIFLUOROMETHYL)PYRIMIDIN 2 YL]PIPERIDINE 3 CARBOXAMIDE; N (4 CYANOPHENETHYL) 1 [4 METHYL 6 (4 METHYLPIPERAZIN 1 YL]PYRIMIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 CYANOPHENETHYL) 1 [5 FLUORO 4 METHYL 6 (4 METHYLPIPERAZIN 1 YL)PYRIMIDIN 2 YL]PIPERIDINE 3 CARBOXAMIDE; N (4 CYANOPHENETHYL) 1 [6 (PIPERAZIN 1 YL) 2 (TRIFLUOROMETHYL)PYRIMIDIN 4 YL]PIPERIDINE 3 CARBOXAMIDE; N (4 CYANOPHENETHYL) 1 [6 [4 (OXETAN 3 YL)PIPERAZIN 1 YL] 2 (TRIFLUOROMETHYL)PYRIMIDIN 4 YL]PIPERIDINE 3 CARBOXAMIDE; N (4 CYANOPHENETHYL)PIPERIDINE 3 CARBOXAMIDE; N (4 FLUOROPHENETHYL) 1 (4 METHYLPYRIMIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; N (4 METHYLPHENETHYL) 1 (PYRIMIDIN 2 YL)PIPERIDINE 3 CARBOXAMIDE; PYRIMIDINE DERIVATIVE; TRIFLUOROMETHYL(PYRIMIDIN 2 YL)AZETIDINE 2 CARBOXAMIDE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG POTENCY; DRUG SOLUBILITY; GLUCOSE BLOOD LEVEL; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; IC 50; IN VIVO STUDY; LIVER MICROSOME; LONG TERM CARE; MALE; MOUSE; NONHUMAN; OBESITY; ORAL GLUCOSE TOLERANCE TEST; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; DRUG DISCOVERY; GLUCAGON-LIKE PEPTIDE 1; HUMANS; HYPOGLYCEMIC AGENTS; MALE; MICE; MICE, INBRED C57BL; MICE, OBESE; PIPERAZINES; RECEPTORS, G-PROTEIN-COUPLED; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84899516119     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401731q     Document Type: Article

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