- 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
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Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.
- Phillips, Dean P.,Gao, Wenqi,Yang, Yang,Zhang, Guobao,Lerario, Isabelle K.,Lau, Thomas L.,Jiang, Jiqing,Wang, Xia,Nguyen, Deborah G.,Bhat, B. Ganesh,Trotter, Carol,Sullivan, Heather,Welzel, Gustav,Landry, Jannine,Chen, Yali,Joseph, Sean B.,Li, Chun,Gordon, W. Perry,Richmond, Wendy,Johnson, Kevin,Bretz, Angela,Bursulaya, Badry,Pan, Shifeng,McNamara, Peter,Seidel, H. Martin
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p. 3263 - 3282
(2014/05/20)
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- Synthesis and evaluation of 2′-substituted 4-(4′-carboxy- or 4′-carboxymethylbenzylidene)-N-acylpiperidines: Highly potent and in vivo active steroid 5α-reductase type 2 inhibitors
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Sixteen compounds derived from N-acyl-4-benzylidenepiperidine-4′-carboxylic acids were synthesized and evaluated for inhibition of rat and human steroid 5α-reductase isozymes types 1 and 2. In the dicyclohexylacetyl series, fluorination in the 2-position of the benzene nucleus (15), exchange of the carboxy group by a carboxymethyl moiety (20), and combination of both structural modifications (25) led to highly active inhibitors of the human type 2 isozyme (IC50 values: 15, 11 nM; 20, 6 nM; 25, 7 nM; finasteride, 5 nM). In vivo all compounds tested markedly reduced the prostate weights in castrated testosterone-treated rats. Oral activity was shown for compound 7. From the finding that compound 15 is active in the rat, although it is a rather poor inhibitor of the rat enzyme and is a strong inhibitor of the human enzyme, it is concluded that it should be highly potent in men.
- Picard, Franck,Barassin, Stephan,Mokhtarian, Armand,Hartmann, Rolf W.
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p. 3406 - 3417
(2007/10/03)
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