Delving into the Latest Updates on GSK-3527497 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

TRPV4

Mechanism

TRPV4 antagonists(Transient receptor potential cation channel subfamily V member 4 antagonists)

Therapeutic Areas

Respiratory DiseasesOther Diseases

Active Indication

Lung Injury

Inactive Indication-

Originator Organization

GlaxoSmithKline LLC

Active Organization

GlaxoSmithKline LLC

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Matthews, Jay M. ; Holt, Dennis A. ; Barton, Linda S. ; McCleland, Brent W. ; Sanchez, Robert M. ; Jolivette, Larry J. ; Lawhorn, Brian G. ; Roethke, Theresa J. ; Patterson, Jaclyn R. ; McAtee, John J. ; Costell, Melissa H. ; Behm, David J. ; Brnardic, Edward J. ; Pero, Joseph E. ; Terrell, Lamont R. ; Brooks, Carl A. ; Rivero, Ralph A. ; Shenje, Raynold

GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CL_u, Vdss_u, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdss_u and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdss_u in addition to bulk physicochemical properties. Optimization of CL_u within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.

100 Deals associated with GSK-3527497

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