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Evaluation of AMG 076, a potent and selective MCHR1 antagonist, in rodent and primate obesity models.

ABSTRACT: Melanin-concentrating hormone (MCH) regulates food intake through activation of the receptor, MCHR1. We have identified AMG 076 as an orally bioavailable potent and selective small molecule antagonist of MCHR1. In mouse models of obesity, AMG 076 caused a reduction in body weight gain in wild-type (MCHR1+/+) but not in knockout (MCHR1-/-) mice. The body weight reduction was associated with decreases in food intake and increases in energy expenditure. Importantly, we show that these MCHR1-dependent effects of AMG 076 were also reflected in improved metabolic phenotypes, increased glucose tolerance and insulin sensitivity. Preliminary data on effects of AMG 076 in obese cynomolgus monkeys are also presented.

SUBMITTER: Motani AS

PROVIDER: S-EPMC4184568 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Evaluation of AMG 076, a potent and selective MCHR1 antagonist, in rodent and primate obesity models.

Motani Alykhan S AS Luo Jian J Liang Lingming L Mihalic Jeffrey T JT Chen Xiaoqi X Tang Liang L Li Leping L Jaen Juan J Chen Jin-Long JL Dai Kang K

Pharmacology research & perspectives 20130917 1

Melanin-concentrating hormone (MCH) regulates food intake through activation of the receptor, MCHR1. We have identified AMG 076 as an orally bioavailable potent and selective small molecule antagonist of MCHR1. In mouse models of obesity, AMG 076 caused a reduction in body weight gain in wild-type (MCHR1+/+) but not in knockout (MCHR1-/-) mice. The body weight reduction was associated with decreases in food intake and increases in energy expenditure. Importantly, we show that these MCHR1-depende ...[more]

PMID: 25505557

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Project description:Objective Glucose-dependent insulinotropic polypeptide (GIP) is one of the two major incretin factors that regulate metabolic homeostasis. Genetic ablation of its receptor (GIPR) in mice confers protection against diet-induced obesity (DIO), while GIPR neutralizing antibodies produce additive weight reduction when combined with GLP-1R agonists in preclinical models and clinical trials. Conversely, GIPR agonists have been shown to promote weight loss in rodents, while dual GLP-1R/GIPR agonists have proven superior to GLP-1R monoagonists for weight reduction in clinical trials. We sought to develop a long-acting, specific GIPR peptide antagonist as a tool compound suitable for investigating GIPR pharmacology in both rodent and human systems. Methods We report a structure–activity relationship of GIPR peptide antagonists based on the human and mouse GIP sequences with fatty acid-based protraction. We assessed these compounds in vitro, in vivo in DIO mice, and ex vivo in islets from human donors. Results We report the discovery of a GIP(5-31) palmitoylated analogue, [Nα-Ac, L14, R18, E21] hGIP(5-31)-K11 (γE-C16), which potently inhibits in vitro GIP-mediated cAMP generation at both the hGIPR and mGIPR. In vivo, this peptide effectively blocks GIP-mediated reductions in glycemia in response to exogenous and endogenous GIP and displays a circulating pharmacokinetic profile amenable for once-daily dosing in rodents. Co-administration with the GLP-1R agonist semaglutide and this GIPR peptide antagonist potentiates weight loss compared to semaglutide alone. Finally, this antagonist inhibits GIP- but not GLP-1-stimulated insulin secretion in intact human islets. Conclusions Our work demonstrates the discovery of a potent, specific, and long-acting GIPR peptide antagonist that effectively blocks GIP action in vitro, ex vivo in human islets, and in vivo in mice while producing additive weight-loss when combined with a GLP-1R agonist in DIO mice. Highlights • [Nα-Ac, L14, R18, E21] hGIP(5-31) - K11 (γE-C16) is a potent and specific GIPR peptide antagonist.• Protraction chemistry and location influences pharmacology, not simply PK profile.• The lead peptide displays a PK profile amenable for once-daily dosing in rodents.• The lead antagonist potentiates GLP-1R agonist mediated weight loss in rodents.• GIP, not GLP-1, action is diminished by the lead antagonist in intact human islets.

Dataset Information

Evaluation of AMG 076, a potent and selective MCHR1 antagonist, in rodent and primate obesity models.

Publications

Evaluation of AMG 076, a potent and selective MCHR1 antagonist, in rodent and primate obesity models.

Similar Datasets

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