title: Chemical and biological investigation of cyclopropyl containing diaryl-pyrazole-3-carboxamides as novel and potent cannabinoid type 1 receptor antagonists.
abstract: 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.
authors.affiliation: Medicinal Chemistry Research Laboratory IV, Gedeon Richter Plc, H-1475 Budapest 10, Hungary. gy.szabo@richter.hu
authors.forename: György
authors.initials: G
authors.lastname: Szabó
authors.forename: Balázs
authors.initials: B
authors.lastname: Varga
authors.forename: Dóra
authors.initials: D
authors.lastname: Páyer-Lengyel
authors.forename: Attila
authors.initials: A
authors.lastname: Szemzo
authors.forename: Péter
authors.initials: P
authors.lastname: Erdélyi
authors.forename: Krisztina
authors.initials: K
authors.lastname: Vukics
authors.forename: Judit
authors.initials: J
authors.lastname: Szikra
authors.forename: Eva
authors.initials: E
authors.lastname: Hegyi
authors.forename: Mónika
authors.initials: M
authors.lastname: Vastag
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.forename: Judit
authors.initials: J
authors.lastname: Laszy
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
authors.forename: János
authors.initials: J
authors.lastname: Fischer
mesh_terms: 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
chemical_list: D019440:Anti-Obesity Agents; D008055:Lipids; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C031280:pyrazole