title: Potential anxiolytic agents. Part 4: novel orally-active N(5)-substituted pyrido[1,2-a]benzimidazoles with high GABA-A receptor affinity.
abstract: 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.
authors.affiliation: Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA 19477-0776, USA. ajordan@prdus.jnj.com
authors.forename: Alfonzo D
authors.initials: AD
authors.lastname: Jordan
authors.forename: Anil H
authors.initials: AH
authors.lastname: Vaidya
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Rosenthal
authors.forename: Barry
authors.initials: B
authors.lastname: Dubinsky
authors.forename: Cheryl P
authors.initials: CP
authors.lastname: Kordik
authors.forename: Pauline J
authors.initials: PJ
authors.lastname: Sanfilippo
authors.forename: Wu-Nan
authors.initials: WN
authors.lastname: Wu
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
mesh_terms: 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
chemical_list: D014151:Anti-Anxiety Agents; D001562:Benzimidazoles; D058785:GABA-A Receptor Agonists; D011725:Pyridines