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.

QRFP-Deficient Mice Are Hypophagic, Lean, Hypoactive and Exhibit Increased Anxiety-Like Behavior

“…Therefore, effects of chronic blockade of QRFP signaling might have complex impact on animals’ body weight homeostasis. Recently, a GPR103 antagonist was shown to acutely decrease food intake in male mice[31]. But long-term effects of QRFP blockade on body weight or other phenotypes have remained unknown.…”

The Arg–Phe‐amide peptide 26RFa/glutamine RF‐amide peptide and its receptor: IUPHAR Review 24

“…However, the IC 50s of the latter compounds in radiobinding assays remain in the same range, that is, IC 50 = 40 nM for compound 10 and IC 50 = 280 nM for compound 11 compared with IC 50 = 70 nM for compound 5. Of note, the IC 50 for compound 5 measured by Georgsson et al (2014) is 10 times higher than the IC 50 for this compound reported in the original patent (IC 50 = 6.1 nM) (Haga et al, 2010a). Preclinical tests revealed for the first time an effect of a QRFP receptor antagonist: in a 3 day automated food intake measurement study, compound 10 ( Figure 11) provoked a significant and dose-dependent reduction on food intake compared to vehicle-treated animals (Georgsson et al, 2014).…”

“…The conformation of 11 used in this superimposition is only 0.8 kcal·mol −1 higher than the lowest energy conformation of 11 identified after optimization by quantum mechanics. These observations suggest that the antagonists designed by Georgsson et al () mimic the C‐terminal Arg 25 –Phe 26 residues of 26RFa/QRFP.…”

“…Structural superposition between 26RFa (20–26) (grey) and compound 11 (pink). Reprinted from Georgsson et al (). Used with permission.…”

“…Consistent with the widespread distribution of the receptor, 26RFa and QRFP have been found to regulate many physiological functions including energy homeostasis (Chartrel et al, ), bone formation (Baribault et al, ), hypothalamo‐pituitary‐gonadal activity (Navarro et al, ; Patel et al, ), insulin secretion (Egido et al, ; Granata et al, ; Prévost et al, ), locomotor activity (Do Rego et al, ) and analgesia (Yamamoto et al, ). The potential implication of these neuropeptides in various pathologies has prompted medicinal chemists to study the structure–activity relationships (SAR) of 26RFa in order to design selective agonists and antagonists (Le Marec et al, ; Neveu et al, , ; Georgsson et al, , ; Nordqvist et al, ).…”