title: GPR103 antagonists demonstrating anorexigenic activity in vivo: design and development of pyrrolo[2,3-c]pyridines that mimic the C-terminal Arg-Phe motif of QRFP26.
abstract: 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.
authors.affiliation: CVMD Medicinal Chemistry, ‡CVMD DMPK, ∥CVMD Bioscience, +Discovery Sciences, and ⊥RIA Medicinal Chemistry, AstraZeneca, Pepparedsleden 1, 431 83 Mölndal, Sweden.
authors.forename: Jennie
authors.initials: J
authors.lastname: Georgsson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bergström
authors.forename: Anneli
authors.initials: A
authors.lastname: Nordqvist
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Watson
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blundell
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Johansson
authors.forename: Annika U
authors.initials: AU
authors.lastname: Petersson
authors.forename: Zhong-Qing
authors.initials: ZQ
authors.lastname: Yuan
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Kristensson
authors.forename: Dorota
authors.initials: D
authors.lastname: Kakol-Palm
authors.forename: Christian
authors.initials: C
authors.lastname: Tyrchan
authors.forename: Eric
authors.initials: E
authors.lastname: Wellner
authors.forename: Udo
authors.initials: U
authors.lastname: Bauer
authors.forename: Peter
authors.initials: P
authors.lastname: Brodin
authors.forename: Anette
authors.initials: A
authors.lastname: Svensson Henriksson
mesh_terms: D020816:Amino Acid Motifs; D001120:Arginine / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010649:Phenylalanine / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D011725:Pyridines; D011758:Pyrroles; C476582:QRFPR protein, human; D043562:Receptors, G-Protein-Coupled; D010649:Phenylalanine; D001120:Arginine