Delving into the Latest Updates on KD-7332 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

NOS2

Mechanism

NOS2 inhibitors(Nitric oxide synthase, inducible inhibitors)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Neuralgia

Originator Organization

Kalypsys, Inc.

Active Organization-

Inactive Organization

Kalypsys, Inc.

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

Author: Nguyen, Phan M. ; Yazdani, Nahid ; Bonnefous, Céline ; Roppe, Jeffrey ; Smith, Nicholas D. ; Rao, Tadimeti S. ; Severance, Daniel ; Symons, Kent T. ; Walsh, John P. ; Zhang, Yan ; Noble, Stewart A. ; Sablad, Marciano ; Rix, Peter ; Rozenkrants, Natasha ; Shiau, Andrew K. ; Zhuang, Hui ; Chen, Xiaohong ; Wang, Li ; Hassig, Christian A. ; Payne, Joseph E.

There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We describe the identification from an ultra high-throughput screen of a novel series of quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies on the screening hit, coupled with an in vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates and drug levels, rapidly led to the identification of compounds 12 and 42--potent inhibitors of the human and mouse iNOS enzyme that were highly selective over endothelial NOS (eNOS). Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model.

100 Deals associated with KD-7332

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