Partnering

Obesity: MCH-1 Antagonists Program Summary

Understanding the Melanin Concentrating Hormone 1 (MCH1) Receptor

Antagonism of the melanin concentrating hormone 1 (MCH1) receptor is a promising new approach for the treatment of obesity. MCH is a potent orexigenic peptide that exerts an effect on food intake and body weight regulation. It is known to stimulate feeding in rats and promote increases in glucose, insulin, and leptin levels, mimicking the human metabolic syndrome. It is also believed to regulate energy homeostasis through neurons in the lateral hypothalamic area of the central nervous system (CNS). Small molecule antagonists of the MCH1 receptor have demonstrated efficacy in rodent models of obesity that rivals currently available therapeutics, suggesting the potential for improved therapy in humans.

Clinical candidate ALB-127158(a) possesses high affinity for the MCH1 receptor and a good in vitro profile with desirable drug-like properties. The in vivo efficacy was demonstrated in a chronic 28-day feeding study in diet-induced obese (DIO) mice. ALB-127158(a) showed excellent weight loss of 12.3% at 5 mg/kg twice daily, 17.3% at 15 mg/kg twice daily and 18.1% at 30 mg/kg once daily (Figure I). The study included positive control sibutramine (20 mg/kg once daily, 7.6% weight loss), a previously marketed serotonin and noradrenaline reuptake inhibitor. Dosing of ALB-127158(a) resulted in a sustained reduction in food intake and a continued gradual weight loss over the course of the 28-day study, unlike the feeding and weight gain rebound observed with positive control sibutramine (Figure II). Body composition analysis of the animals after the conclusion of the experiment demonstrated that the weight loss seen for ALB-127158(a) was associated with exclusive loss in fat mass (Figure III). Circulating plasma levels of the energy regulating hormone leptin decreased concomitant with reduction in body fat (Figure IV).

AMRI also has discovered additional series of MCH1 antagonists as backup candidates with good in vitro profiles, desirable drug-like properties, and potent in vivo activity in rodent models of obesity. Key features of AMRI’s MCH1 receptor antagonists include the following:

  • High potency MCH1 antagonists with tractable structure activity relationships (SAR)
  • Good in vitro ADME properties
  • Good off-target receptor selectivity
  • Good oral pharmacokinetics and robust MCH1 receptor occupancy in the CNS (see figure below)
  • In vivo efficacy demonstrated in DIO mouse feeding studies for lead compounds
  • Multiple patent applications filed to protect AMRI intellectual property

image

The images show binding of a novel tritiated AMRI compound to the caudate/putamen and nucleus accumbens in rat brain.

Understanding the Melanin Concentrating Hormone 1 (MCH1) Receptor:

Antagonism of the melanin concentrating hormone 1 (MCH1) receptor is a promising new approach for the treatment of obesity. MCH is a potent orexigenic peptide that exerts an effect on food intake and body weight regulation. It is known to stimulate feeding in rats and promote increases in glucose, insulin and leptin levels, mimicking the human metabolic syndrome. It is also believed to regulate energy homeostasis through neurons in the lateral hypothalamic area of the central nervous system (CNS). Small molecule antagonists of the MCH1 receptor have demonstrated efficacy in rodent models of obesity that rivals currently available therapeutics, suggesting the potential for improved therapy in humans.

For more information, download the following posters pertaining to MCH1 Receptors: