Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative library synthesis approach delivered the first select...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-01, Vol.20 (2), p.558-562
Hauptverfasser:	Bridges, Thomas M, Kennedy, J Phillip, Cho, Hyekyung P, Breininger, Micah L, Gentry, Patrick R, Hopkins, Corey R, Conn, P Jeffrey, Lindsley, Craig W
Format:	Artikel
Sprache:	eng
Schlagworte:	Allosteric Regulation Animals CHO Cells Cricetinae Cricetulus Drug Design High-Throughput Screening Assays Mice Mice, Knockout Receptor, Muscarinic M1 - agonists Receptor, Muscarinic M1 - chemistry Receptor, Muscarinic M1 - metabolism Receptor, Muscarinic M3 - agonists Receptor, Muscarinic M3 - metabolism Receptor, Muscarinic M5 - agonists Receptor, Muscarinic M5 - metabolism Structure-Activity Relationship
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Zusammenfassung:	This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative library synthesis approach delivered the first selective M(5) PAM (no activity at M(1)-M(4) @ 30microM), and an important tool compound to study the role of M(5) in the CNS.
ISSN:	1464-3405
DOI:	10.1016/j.bmcl.2009.11.089