Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship

Donn G Wishka; Daniel P Walker; Karen M Yates; Steven C Reitz; Shaojuan Jia; Jason K Myers; Kirk L Olson; E Jon Jacobsen; Mark L Wolfe; Vincent E Groppi; Alexander J Hanchar; Bruce A Thornburgh; Luz A Cortes-Burgos; Erik H F Wong; Brian A Staton; Thomas J Raub; Nicole R Higdon; Theron M Wall; Raymond S Hurst; Rodney R Walters; William E Hoffmann; Mihaly Hajos; Stanley Franklin; Galen Carey; Lisa H Gold; Karen K Cook; Steven B Sands; Sabrina X Zhao; John R Soglia; Amit S Kalgutkar; Stephen P Arneric; Bruce N Rogers

doi:10.1021/jm0602413

Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship

J Med Chem. 2006 Jul 13;49(14):4425-36. doi: 10.1021/jm0602413.

Affiliation

¹ Pfizer Global Research & Development, Eastern Point Road, Groton, Connecticut 06340, USA.

PMID: 16821801
DOI: 10.1021/jm0602413

Abstract

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.

MeSH terms

Animals
Biological Availability
Brain / metabolism
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cognition Disorders / drug therapy*
Drug Stability
Ether-A-Go-Go Potassium Channels / drug effects
Evoked Potentials, Auditory / drug effects
Humans
In Vitro Techniques
Learning / drug effects
Male
Memory / drug effects
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Neurons / drug effects
Neurons / physiology
Nicotinic Agonists / chemical synthesis*
Nicotinic Agonists / pharmacokinetics
Nicotinic Agonists / pharmacology
Nootropic Agents / chemical synthesis*
Nootropic Agents / pharmacokinetics
Nootropic Agents / pharmacology
Patch-Clamp Techniques
Quinuclidines / chemical synthesis*
Quinuclidines / chemistry
Quinuclidines / pharmacology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptors, Nicotinic / metabolism*
Receptors, Nicotinic / physiology
Recognition, Psychology / drug effects
Schizophrenia / drug therapy*
Stereoisomerism
Structure-Activity Relationship
alpha7 Nicotinic Acetylcholine Receptor

Substances

Bridged Bicyclo Compounds, Heterocyclic
Chrna7 protein, human
Chrna7 protein, rat
Ether-A-Go-Go Potassium Channels
N-(1-azabicyclo(2.2.2)oct-3-yl)furo(2,3-c)pyridine-5-carboxamide
Nicotinic Agonists
Nootropic Agents
Quinuclidines
Receptors, Nicotinic
alpha7 Nicotinic Acetylcholine Receptor