Potential anxiolytic agents. Part 4: novel orally-active N(5)-substituted pyrido[1,2-a]benzimidazoles with high GABA-A receptor affinity.
A series of pyrido[1,2-a]benzimidazoles (PBIs) with substitution on the N(5)-nitrogen has been synthesized and found to possess high affinity for the benzodiazepine (BZD) site on the GABA-A receptor. The compounds evaluated include those bearing a heteroalkyl group and heterocyclic rings. The most promising of these compounds is ethoxymethyl analogue 24, which has an IC(50) of 0.1 nM for the BZD site on the GABA-A receptor and has been advanced to human clinical trials.
Jordan
Alfonzo D
AD
Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA 19477-0776, USA. ajordan@prdus.jnj.com
Vaidya
Anil H
AH
Rosenthal
Daniel I
DI
Dubinsky
Barry
B
Kordik
Cheryl P
CP
Sanfilippo
Pauline J
PJ
Wu
Wu-Nan
WN
Reitz
Allen B
AB
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D003220:Conflict, Psychological; D058785:GABA-A Receptor Agonists; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D001562:Benzimidazoles; D058785:GABA-A Receptor Agonists; D011725:Pyridines