Dec 13, 2016

Challenges in the development of an M4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs

Bioorganic & Medicinal Chemistry Letters
Michael R WoodCraig W Lindsley

Abstract

This letter describes the chemical optimization of a novel series of M4positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).

Mentioned in this Paper

In Vivo
Thiophenes
Pyridazine
Dmpk
Structure-Activity Relationship
Thienopyridines
Analog
Profile (Lab Procedure)
Protein kinase modulator
DMPK Gene Analysis

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