The discovery of VU0486846: steep SAR from a series of M PAMs based on a novel benzomorpholine core
AUTHORS
Bertron
JLJeanette L ,
Cho
HPHyekyung P ,
Garcia-Barrantes
PMPedro M ,
Panarese
JDJoseph D ,
Salovich
JMJames M ,
Nance
KDKellie D ,
Engers
DWDarren W ,
Rook
JMJerri M ,
Blobaum
ALAnna L ,
Niswender
CMColleen M ,
Stauffer
SRShaun R ,
Conn
PJP Jeffrey ,
Lindsley
CWCraig W .
Bioorganic & medicinal chemistry letters. 2018 5 5; 28(12).
2175-2179
- PMID: 29754948[PubMed].
ABSTRACT
This letter describes the chemical optimization of a new series of M positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).
Tags: 2018