Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases.

The oxycyclohexyl acid BMS-986278 () is a potent lysophosphatidic acid receptor 1 (LPA) antagonist, with a human LPA of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA antagonist clinical compound BMS-986020 (), which culminated in the discovery of , are discussed.

Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119.

G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic β-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes.

Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT(2C) receptor agonists.

The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy.

Synthesis and SAR of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones as 5-HT2C receptor agonists.

A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT(2C) agonism with excellent selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.

Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents.

Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described.

Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.

Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A.