Exploring SAR features in diverse library of 4-cyanomethyl-pyrazole-3-carboxamides suitable for further elaborations as CB1 antagonists.
A chemically diverse library of secondary and tertiary 4-cyanomethyl-1,5-diphenyl-1H-pyrazole-3-carboxamides was synthesized to enable mapping of the SAR, in the eastern amide region, with regard to CB1 antagonist activity, This study was initiated as a prelude to the design and synthesis of possible CB1 antagonists that do not readily pass the blood-brain-barrier. In general a range of modifications were found to be tolerated in this part of the molecule, although polar and especially charged groups did to a degree reduce the CB1 antagonistic activity. Several compounds with single-digit or even sub-nanomolar potency, suitable for further elaboration of the nitrile moiety, were identified.
Cooper
Martin
M
7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
Receveur
Jean-Marie
JM
Bjurling
Emelie
E
Nørregaard
Pia K
PK
Nielsen
Peter Aadal
PA
Sköld
Niklas
N
Högberg
Thomas
T
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D006801:Humans; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D000577:Amides; D043884:Receptor, Cannabinoid, CB1; D054852:Small Molecule Libraries