Exploration of phenylpropanoic acids as agonists of the free fatty acid receptor 4 (FFA4): Identification of an orally efficacious FFA4 agonist.

The long chain free fatty acid receptor 4 (FFA4/GPR120) has recently been recognized as lipid sensor playing important roles in nutrient sensing and inflammation and thus holds potential as a therapeutic target for type 2 diabetes and metabolic syndrome. To explore the effects of stimulating this receptor in animal models of metabolic disease, we initiated work to identify agonists with appropriate pharmacokinetic properties to support progression into in vivo studies. Extensive SAR studies of a series of phenylpropanoic acids led to the identification of compound 29, a FFA4 agonist which lowers plasma glucose in two preclinical models of type 2 diabetes.

Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1.

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.

6-(4-chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-based melanin-concentrating hormone receptor 1 antagonist.

Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.

Biphenyl amides and isosteres as MCH R1 antagonists.

The pursuit of MCH R1 antagonists for the treatment of obesity has become an active area of research for many pharmaceutical companies. The evidence supporting the use of MCH R1 antagonists for the treatment of obesity is ample, and the recent demonstration of MCH R1 antagonists' efficacy in animal models of obesity has served to augment earlier studies involving MCH peptide and transgenic animals. We report herein our search for MCH R1 antagonists from the discovery of a biphenyl amide by high throughput screening, through the optimization of the biphenyl amide to a series of constrained aryl-substituted thienopyrimidinones, and extending the application of the thienopyrimidinone substructure to other series of MCH R1 antagonists. Importantly, these MCH R1 antagonists have demonstrated efficacy in animal models of obesity through once-daily oral administration at low doses.

The discovery and optimization of pyrimidinone-containing MCH R1 antagonists.

Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented.

Novel benzimidazole-based MCH R1 antagonists.

The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.

Optimization of the 4-aryl group of 4-aryl-pyridine glucagon antagonists: development of an efficient, alternative synthesis.

A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4'-fluoro-2'-hydroxy analogue 33, IC50=190 nM). For efficient preparation of 2'-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.

Integration of optimized substituent patterns to produce highly potent 4-aryl-pyridine glucagon receptor antagonists.

Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-hydroxyethyl] and a 2'-hydroxy group. Due to restricted rotation of the phenyl-pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC(50)=10-25 nM.