Discovery of orally efficacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureas.

Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.

Effects of a selective melanin-concentrating hormone 1 receptor antagonist on food intake and energy homeostasis in diet-induced obese mice.

Melanin concentrating hormone (MCH) is a cyclic neuropeptide expressed in the lateral hypothalamus that plays an important role in energy homeostasis. To investigate the pharmacological consequences of inhibiting MCH signaling in murine obesity models, we examined the effect of acute and chronic administration of a selective MCH1 receptor antagonist (SCH-A) in diet-induced obese (DIO) and Lep(ob/ob) mice. Oral administration of SCH-A for 5 consecutive days (30 mg/kg q.d.) produced hypophagia, a loss of body weight and adiposity, and decreased plasma leptin levels in DIO mice, and hypophagia and reduced weight gain in Lep(ob/ob) mice. Chronic administration of SCH-A to DIO mice decreased food intake, body weight and adiposity, and plasma leptin and free fatty acids. These effects were accompanied by increases in several hypothalamic neuropeptides. Acute administration of SCH-A (30 mg/kg) prevented the decrease in energy expenditure associated with food restriction. These results indicate that MCH1 receptor antagonists may be effective in the treatment of obesity.

Discovery of bicycloalkyl urea melanin concentrating hormone receptor antagonists: orally efficacious antiobesity therapeutics.

Melanin concentrating hormone (MCH) is involved in regulation of food intake and energy homeostasis. Antagonists of the MCH receptor are expected to affect food intake and weight gain, making MCH-R1 an attractive target for obesity treatment. Herein, we report the discovery of a novel, orally active series of MCH-R1 antagonists that exhibit in vivo efficacy in rodent obesity models.

Tetrahydroquinoline sulfonamides as gamma-secretase inhibitors.

The development of a novel series of tetrahydroquinoline-derived gamma-secretase inhibitors for the potential treatment of Alzheimer's disease is described.

2,6-Disubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitors.

A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.

Bicyclo[3.1.0]hexyl urea melanin concentrating hormone (MCH) receptor-1 antagonists: impacting hERG liability via aryl modifications.

Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series.

Bicyclic[4.1.0]heptanes as phenyl replacements for melanin concentrating hormone receptor antagonists.

Melanin concentrating hormone (MCH) receptor antagonists have been proposed as potential treatments of obesity. MCH receptor antagonists with a biphenylamine subunit have been reported previously at Schering-Plough. Herein, we report the discovery of bicyclo[4.1.0]heptanes as replacements for the middle phenyl ring of the biphenylamine moiety in order to eliminate its potential mutagenic liability. Structure-activity relationships in this series were found to be very similar to those of the original biphenylamine series, suggesting that the two series have similar binding modes.

Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED.

In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.

Synthesis and antifungal activity of the 2,2,5-tetrahydrofuran regioisomers of SCH 51048.

The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen at only one of the two possible ring positions benzylic to the difluorobenzene participates usefully in active site binding.