Novel thioamide derivatives as neutral CB1 receptor antagonists.
A novel class of cannabinoid-1 (CB1) receptor antagonists for the treatment of obesity is presented. The carboxamide linker in a set of 5,6-diaryl-pyrazine-2-amide derivatives was transformed into the corresponding thioamide, by using a one-pot synthesis. The structural series of thioamides not only showed retained CB1 potency (below 10nM), but also showed improved solubility. In addition, the neutral antagonist 2c significantly reduced body weight in cafeteria diet obese mice.
Boström
Jonas
J
Lead Generation Department, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. dr.jonas.bostrom@gmail.com
Olsson
Roine I
RI
Tholander
Joakim
J
Greasley
Peter J
PJ
Ryberg
Erik
E
Nordberg
Henrik
H
Hjorth
Stephan
S
Cheng
Leifeng
L
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy; D011719:Pyrazines / Q000737:chemistry* / Q000493:pharmacokinetics; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013854:Thioamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D019440:Anti-Obesity Agents; D011719:Pyrazines; D043884:Receptor, Cannabinoid, CB1; D013854:Thioamides