Rational design of a novel peripherally-restricted, orally active CB(1) cannabinoid antagonist containing a 2,3-diarylpyrrole motif.
A new series of 2,3-diarylpyrroles have been prepared and evaluated as CB(1) antagonists. Modulation of the topological polar surface area allowed the identification of high affinity peripherally-restricted CB(1) antagonists. Compound 11, obtained after further optimization of the metabolic profile displayed very low brain penetration, yet was able to reverse CP55940-induced gastrointestinal transit inhibition following oral administration.
Hortala
Laurent
L
Exploratory Unit, Sanofi-aventis R&D, 371 rue du Professeur Joseph Blayac, Montpellier, France.
Rinaldi-Carmona
Murielle
M
Congy
Christian
C
Boulu
Laurent
L
Sadoun
Freddy
F
Fabre
Gérard
G
Finance
Olivier
O
Barth
Francis
F
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D005772:Gastrointestinal Transit / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant
D010880:Piperidines; D011720:Pyrazoles; D011758:Pyrroles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant