Potent, Selective, and Orally Efficacious Antagonists of Melanin-Concentrating Hormone Receptor 1

Abstract

The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.

Anti-obesity effects of small molecule melanin-concentrating hormone receptor1 (MCHR1) antagonists

“…No specifics were provided, but it was reported that compound 6 was profiled against a battery of 7TM receptors, enzymes and ion channels with no significant off-target activity of note (Taveres et al, 2006b). They also reported an approximate 6700-fold selectivity for compound 7 binding to MCHR1 compared to the hERG patch clamp IC 50 (Tavares et al, 2006b).…”

Super-secondary structure peptidomimetics: design and synthesis of an α–α hairpin analogue

“…35 Condensation with 1,3-diaminopropane provided di-imine 4 as a reactive intermediate. Addition of commercially available tetrakis(acetonitrile)palladium(II) tetrafluoroborate gave complex 5 , with an immediate chromatic change of the reaction mixture from yellow to dark orange-brown.…”

Biphenyl Amides and Isosteres as MCH R1 Antagonists

“…The efficacy of compound 96 in inducing weight loss was evaluated in a high fat (58% kcal of fat, Research Diets #D12331) DIO AKR/J mouse model described previously for compounds 10 and 65. During a 26-day treatment, oral administration of compound 90 at 1, 3 and 10 mg/kg once daily caused a sustained dosedependent weight loss of 4.8%, 9.4% and 16.9% respectively, relative to vehicle controls [33].…”