Comparative pharmacology of AMR-MCH-1 and AMR-MCH-2, MCH1 receptor antagonists for the treatment of obesity

Bruce Sargent1, Matthew Surman1, Emily Freeman1, James Grabowski1, Xiao-Wu Jiang1, Guowei Jiang1, Mark Hadden1, Michele Luche1, Yuri Khmelnitsky1, John Lindsay1, Lyuda Mozhaeva1, Julianne Zaremba1, Jean Viggers2, Steve Vickers2, Simon Goddard2, Sharon Cheetham2, Peter Guzzo1

1AMRI, Albany, New York, USA, 2RenaSci Consultancy Ltd, Nottingham, UK

Melanin-concentrating hormone (MCH) is a cyclic, 19 amino acid neuropeptide. In mammals, MCH is highly expressed in the zona incerta and lateral hypothalamus and regulates food intake and energy homeostasis through interaction with the MCH1 receptor (Collins, et al., 2003; Skofitsch et al., 1985). Antagonists of the MCH1 receptor have been shown to be a promising new approach for the treatment of obesity (Collins, et al., 2003; McBriar, 2006).

AMR-MCH-1 (4-(benzyloxy)-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-one) is representative of a novel structural class of selective, high affinity MCH1 receptor antagonists identified by AMRI (Sargent, et al. 2008). AMR-MCH-1 was found to bind to the human MCH1 receptor with a Ki value of 2.6 nM and determined to be a functional antagonist at the MCH1 receptor with an IC50 value of 14 nM in an aequorin-based Ca2+ mobilization assay. AMR-MCH-1 demonstrated significant and sustained reductions in food intake and body weight in a chronic, 28-day feeding study in male dietary-induced obese (DIO) C57BL/6J mice (diet D12451). At twice daily oral doses of 30 mg/kg and 60 mg/kg, AMR-MCH-1 produced weight losses of 11.1% and 13.9%, respectively, compared with 5.8% for positive control sibutramine (20 mg/kg po qd). AMR-MCH-1 also caused sustained reduction in weekly food intake (by 24% and 22% in week 1; 11% and 12% in week 2; and 12% and 7% in week 3 for 30 mg/kg and 60 mg/kg, respectively; non-significant reductions were observed in week 4). Fat pad analysis indicated that the weight loss caused by AMR-MCH-1 was associated with reductions in fat mass of 27.5% and 44.6% compared to vehicle for the 30 mg/kg bid and 60 mg/kg bid dose groups, respectively. The brain levels of AMR-MCH-1 at the 6 hour time point following the final dose were found to be 1,377 ng/g and 3,226 ng/g for the 30 and 60 mg/kg bid doses, corresponding to brain to plasma ratios of 0.72 and 0.86, respectively. Improved brain penetration was achieved through a modified structural class, represented by AMR-MCH-2 (2-(4-chlorophenyl)-5-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)furo[3,2-c]pyridin-4(5H)-one). AMR-MCH-2 maintained high affinity for the MCH1 receptor, with a Ki value of 5.2 nM and a functional IC50 antagonist value of 23 nM. AMR-MCH-2 demonstrated improved efficacy versus AMR-MCH-1 in 5-day feeding studies in DIO mice with once a day oral dosing (qd). At 30 mg/kg qd, AMR-MCH-2 showed 4.5% weight loss compared to the 2.8% weight loss provided by AMR-MCH-1 at twice the dose (60 mg/kg qd). The improved efficacy was correlated with increased brain exposure. At 6 hours following a single 10 mg/kg oral dose of AMR-MCH-2, DIO mice were found to have brain concentrations of 2,253 ng/g with a brain to plasma ratio of 16. These data indicate that AMR-MCH-1 is a high affinity MCH1 receptor antagonist that causes sustained weight loss in obese mice and that structural modification to AMR-MCH-2 yields improved brain penetration and improved efficacy.

Collins, C.A. et al. (2003) Curr. Opin. Investig. Drugs 4(4), 386–394.

McBriar, M.D. (2006)Curr. Opin. Drug Disc. & Dev. 9, 496–508.

Sargent, B.J. et al. (2008) Society for Neuroscience Annual Meeting, Abstract 584.25/SS6.

Skofitsch, G. et al. (1985) Brain Res. Bull. 15, 635–649.