Delving into the Latest Updates on ML326 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

ML326, VU0467903

Target

M5 receptor

Action

positive allosteric modulator

Mechanism

M5 receptor positive allosteric modulator(Muscarinic acetylcholine receptor M5 positive allosteric modulator)

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

Vanderbilt University Medical Center

Active Organization-

Inactive Organization

Vanderbilt University Medical Center

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Author: Lindsley, Craig W. ; Smith, Emery ; Hodder, Peter S. ; Lindsley, Craig W ; Engers, Julie L. ; Niswender, Colleen M. ; Vinson, Paige N. ; Wood, Michael R. ; Daniels, J Scott ; Wood, Michael R ; Niswender, Colleen M ; Chase, Peter ; Bridges, Thomas M ; Bridges, Thomas M. ; Gentry, Patrick R. ; Engers, Julie L ; Lamsal, Atin ; Vinson, Paige N ; Conn, P Jeffrey ; Jeffrey Conn, P. ; Scott Daniels, J. ; Hodder, Peter S

This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30μM) and a robust 20-fold leftward shift of the ACh CRC.

100 Deals associated with ML326

Login to view more data