Georgsson J.,CVMD Medicinal Chemistry |
Bergstrom F.,CVMD DMPK |
Nordqvist A.,CVMD Medicinal Chemistry |
Watson M.J.,C4X Discovery |
And 12 more authors.
Journal of Medicinal Chemistry | Year: 2014
GPR103, a G-protein coupled receptor, has been reported to have orexigenic properties through activation by the endogenous neuropeptide ligands QRFP26 and QRFP43. Recognizing that central administration of QRFP26 and QRFP43 increases high fat food intake in rats, we decided to investigate if antagonists of GPR103 could play a role in managing feeding behaviors. Here we present the development of a new series of pyrrolo[2,3-c]pyridines as GPR103 small molecule antagonists with GPR103 affinity, drug metabolism and pharmacokinetics and safety parameters suitable for drug development. In a preclinical obesity model measuring food intake, the anorexigenic effect of a pyrrolo[2,3-c]pyridine GPR103 antagonist was demonstrated. In addition, the dynamic 3D solution structure of the C-terminal heptapeptide of the endogenous agonist QRFP26 (20-26) was determined using NMR. The synthetic pyrrolo[2,3-c] pyridine antagonists were compared to this experimental structure, which displayed a possible overlay of pharmacophore features supportive for further design of GPR103 antagonists. © 2014 American Chemical Society. Source