Delving into the Latest Updates on AZ-GHS-22 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

GHSR

Action

antagonists

Mechanism

GHSR antagonists(Ghrelin/growth hormone secretagogue receptor antagonists)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Obesity

Inactive Indication-

Originator Organization

AstraZeneca R&D Charnwood

Active Organization

AstraZeneca R&D Charnwood

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC27H33ClN6O5S2

InChIKeyXWFQFKFKWKWIEW-UHFFFAOYSA-N

CAS Registry1143020-91-0

Author: Holmes, Jane L. ; Newcombe, Nicholas J. ; Moore, Jane E. ; Masters, David ; Clarke, David S. ; Bowker, Suzanne S. ; Stokes, Stephen ; McCoull, William ; Green, Clive ; Ertan, Anne ; Robb, Graeme R. ; Brown, Alastair J. H. ; Morgan, David ; Fenwick, Mark ; Newton, Claire ; Pointon, Helen ; Barton, Peter ; Sheldon, Christopher ; Cameron, Jennifer ; Dossetter, Alexander G. ; Davies, Robert D. M. ; Martin, Nathaniel

Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.

100 Deals associated with AZ-GHS-22

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