Peripherally restricted CB1 receptor inverse agonists hold potential as useful therapeutics to treat obesity and related metabolic diseases without causing undesired CNS-mediated adverse effects. We identified a series of tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and highly peripherally selective CB1 receptor inverse agonists. This discovery was achieved by introducing polar functional groups into the molecule, which increase the topological polar surface area and reduce its brain-penetrating ability.

A series of potent and receptor-selective cannabinoid-1 (CB1) receptor inverse agonists has been discovered. Peripheral selectivity of the compounds was assessed by a mouse tissue distribution study, in which the concentrations of a test compound in both plasma and brain were measured. A number of peripherally selective compounds have been identified through this process. Compound 2p was further evaluated in a 3-week efficacy study in the diet-induced obesity (DIO) mouse model. Beneficial effects on plasma glucose were observed from the compound-treated mice.

A series of arylglycine-based analogs was synthesized and tested for TRPM8 antagonism in a cell-based functional assay. Following structure-activity relationship studies in vitro, a number of compounds were identified as potent TRPM8 antagonists and were subsequently evaluated in an in vivo pharmacodynamic assay of icilin-induced 'wet-dog' shaking in which compound 12 was fully effective. TRPM8 antagonists of the type described here may be useful in treating pain conditions wherein cold hypersensitivity is a dominant feature.

L'invention porte sur des composes, des compositions et des procedes pour le traitement de diverses maladies, divers syndromes, diverses affections et divers troubles, dont la douleur. De tels composes sont representes par la formule (I), comme suit : dans laquelle A, B, L, Q, R- 1, R 2 , et R 3 sont tels que definis dans la description.

Monocyte chemoattractant protein-1 (MCP-1) is a major chemoattractant for monocytes and memory T cells by means of their binding to its specific cell-surface receptor, CC-chemokine receptor-2 (CCR2). CCR2 belongs to the G-protein-coupled seven-transmembrane receptor superfamily. The evidence in favor of CCR2 and MCP-1 having dominant roles in monocyte chemotaxis and chronic inflammation was provided by CCR2 and MCP-1 knockout mice. It has been recognized that CCR2 antagonists are potential therapeutic agents in preventing, treating, or ameliorating a CCR2-mediated inflammatory syndrome or disease such as psoriasis, uveitis, rheumatoid arthritis, multiple sclerosis, asthma, obesity, and chronic obstructive pulmonary disease. This review summarizes recent developments in small-molecule CCR2 antagonists disclosed by patent applications published between 2005 and 2008 and related publications.

The synthesis and structure-activity relationship of a series of 7-azaindole piperidine derivatives are described. SAR studies led to the discovery of the potent CCR2 antagonists displaying IC(50) values in the nanomolar range. The representative compound 15 showed reasonable P450 and pharmacokinetics profile.

The synthesis and biological evaluation of a series of substituted dipiperidine alcohols are described. Structure-activity relationship studies led to the discovery of potent CCR2 antagonists displaying IC(50) values in the nanomolar or subnanomolar range. The cinnamoyl compounds had higher binding affinities than the corresponding urea analogs.

A series of phenyl piperidine derivatives possessing potent and selective CCR2 antagonist activity is reported. Structure-activity relationship (SAR) studies have established that incorporation of a second ring system adjacent to the aryl piperidine plays an important role in determining the CCR2 potency. Both a second piperidine ring and a 1,3-substituted cyclopentylamine have been probed as linkers. For the cyclopentylamine series, the 1S,3R-configuration exhibits much higher affinity for hCCR2 than the 1R,3S-configuration. Compound 3g shows good selectivity over CCR1, CCR3, 5-HT and has an excellent P450 profile.