Delving into the Latest Updates on U-89267 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

GABRA1 inhibitors(gamma-aminobutyric acid type A receptor subunit alpha1 inhibitors), GABRB2 inhibitors(gamma-aminobutyric acid type A receptor subunit beta2 inhibitors), GABRG2 inhibitors(gamma-aminobutyric acid type A receptor subunit gamma2 inhibitors)

Therapeutic Areas

Other Diseases

Active Indication-

Inactive Indication

Anxiety Disorders

Originator Organization

Pharmacia & Upjohn Co., Inc.

Active Organization-

Inactive Organization

Pharmacia & Upjohn Co., Inc.

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC18H15N5O2

InChIKeyKIGZWNHARYMTNM-UHFFFAOYSA-N

CAS Registry180989-85-9

A series of tetracyclic imidazoquinoxaline analogs was developed which constrain the carbonyl group of the partial agonist 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-[(dimethylamino)carbonyl] - 4,5-dihydroimidazo[1,5-alpha]quinoxaline (2, U-91571) away from the benzene ring. These analogs orient the carbonyl group in the opposite direction of the previously reported full agonist 1-(5- cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydroimidazo[1,5- alpha]pyrrolo [2,1-c]quinoxalin-10(11H)-one (3, U-89267). A number of approaches were utilized to form the "bottom" ring of this tetracyclic ring system including intramolecular cyclizations promoted by Lewis acids or base, as well as metal-carbenoid conditions. The size and substitution pattern of the additional ring was widely varied. Analogs within this series had high affinity for the benzodiazepine receptor on the alpha-aminobutyric acid A chloride ion channel complex. From TBPS shift and Cl- current assays, the in vitro efficacy of compounds within this class ranged from antagonists to partial agonists with only 18a identified as a full agonist. Additionally, several analogs were quite potent at antagonizing metrazole-induced seizures indicating possible anticonvulsant or anxiolytic activity. Unlike 3, analogs in this series did not have high affinity for the diazepam insensitive alpha 6 beta 2 delta 2 subtype. These results suggest that either constraining the carbonyl group away from the benzene ring or the greater planarity that results from the additional cyclic structure provides analogs with partial agonist properties and prevents effective interaction with the alpha 6 beta 2 delta 2 subtype.

100 Deals associated with U-89267

Login to view more data