Chemical and biological investigation of cyclopropyl containing diaryl-pyrazole-3-carboxamides as novel and potent cannabinoid type 1 receptor antagonists.
Obesity is a major clinical problem in the western world, and many molecular targets have been explored in the search for effective therapeutic agents. One of these, antagonism of the cannabinoid 1 (CB1) receptor, rose to prominence following reports demonstrating the positive modulation of food intake by the CB1 antagonist, rimonabant (3) (SR141716A). In the present study, various diaryl-pyrazole derivatives containing cycloalkyl building blocks were synthesized and tested for CB1 receptor binding affinities. Thorough structure-activity relationship (SAR) studies to optimize the pyrazole substituents led to several novel CB1 antagonists with K(i) <or= 5 nM and with acceptable metabolic stability with human liver microsomes. Among these analogues, we identified 5-(4-cyclopropylphenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-pyrrolidin-1-yl-1H-pyrazole-3-carboxamide (11r), which exhibited a favorable pharmacological profile with outstanding efficacy in reducing serum lipid parameters of metabolic syndrome compared to clinical references.
Szabó
György
G
Medicinal Chemistry Research Laboratory IV, Gedeon Richter Plc, H-1475 Budapest 10, Hungary. gy.szabo@richter.hu
Varga
Balázs
B
Páyer-Lengyel
Dóra
D
Szemzo
Attila
A
Erdélyi
Péter
P
Vukics
Krisztina
K
Szikra
Judit
J
Hegyi
Eva
E
Vastag
Mónika
M
Kiss
Béla
B
Laszy
Judit
J
Gyertyán
István
I
Fischer
János
J
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002417:Cattle; D015195:Drug Design; D004435:Eating / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000097:blood; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; D008055:Lipids; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C031280:pyrazole