Design of a Potent CB₁ Receptor Antagonist Series: Potential Scaffold for Peripherally-Targeted Agents

Abstract

Antagonism of cannabinoid-1 (CB 1 ) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB 1 -mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB 1 receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure−activity-relationship analysis of a novel bicyclic scaffold (3) that exhibits potent CB 1 receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB 1 receptor antagonists.

New role of phenothiazine derivatives as peripherally acting CB1 receptor antagonizing anti-obesity agents

“…Previous studies have revealed that peripheral cannabinoid CB1 receptor blockage is sufficient enough to suppress food intake 26 , increase energy expenditure and reduce lipogenesis in both liver and adipose tissues 27 , 28 . A number of scaffolds especially diaryl heterocyclic compounds such as pyrazoles 34 – 38 , pyrroles 39 , 40 , pyrazolines 41 , 42 , purines 43 , 44 , tetrahydroindazoles 45 , tetrahydropyrazolo[4,3- c ]pyridines 46 etc. have been tried as CB1 receptor antagonists acting peripherally with lower CNS side effects but, unfortunately none of these compounds could make it to the market till date.…”

Regioselective Preparation of Saturated Spirocyclic and Ring-Expanded Fused Pyrazoles

“…Isolated as a white gum (54.6 mg, 0.186 mmol, 74%) from 2n, according to general procedure C: 1 H NMR δ 0.89 (3H, app q, J 7.4 Hz), 1.33 (2H, quint, J 7.9 Hz), 1.48 (9H, s), 1.53 (2H, q, J 7. 6 3-Phenyl-4,5,7,8-tetrahydro-2H-oxepino [4,5-c]pyrazole (3o). Isolated as a white amorphous solid (45.8 mg, 0.214 mmol, 86%) from 2o, according to general procedure C: 1 H NMR δ 2.77 (2H, dd, J 5.0, 4.9 Hz), 2.84 (2H, dd, J 5.0, 4.9 Hz), 3.75 (2H, dd, J 5.1, 5.0 Hz), 3.79 (2H, dd, J 5.0, 4.9 Hz), 7.34 (1H, t, J 7.3 Hz), 7.39 (2H, t, J 7.1 Hz), 7.44 (2H, d, J 7.0 Hz), 10.52 (1H, br); 13…”

Strategies for the generation, validation and application ofin silicoADMET models in lead generation and optimization

“…However, rather few medicinal chemistry papers have been reported in the literature that describe the application of such models. Some examples include the design of a CB1 receptor antagonist series with reduced central nervous system (CNS) activity by focusing on high Polar Surface Area (PSA) [75], the reduction of P-glycoprotein (P-gp) efflux in b-secretase inhibitors by masking known recognition features [76], and the design of histamine H3 receptor antagonist with reduced hERG using 3D-based models [77].…”