Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X sub(7 receptor)

The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X sub(7 receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd) sub(s)s. Multi parametric optimization led to identification of pyrazole 39 as a viable le...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-09, Vol.21 (18), p.5475-5479
Main Authors: Subramanyam, Chakrapani, Duplantier, Allen J, Dombroski, Mark A, Chang, Shang-Poa, Gabel, Christopher A, Whitney-Pickett, Carrie, Perregaux, David G, Labasi, Jeff M, Yoon, Kwansik, Shepard, Richard M, Fisher, Michael
Format: Article
Language:English
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Summary:The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X sub(7 receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd) sub(s)s. Multi parametric optimization led to identification of pyrazole 39 as a viable lead with excellent potency and oral bioavailability. Further attempts to improve the low Vd sub(ss of 39 via introduction of amines led to analogs 40 and 41 which maintained the favorable pharmacology profile of 39 and improved Vd) sub(s)s after iv dosing. But these analogs suffered from poor oral absorption, probably driven by poor permeability.
ISSN:0960-894X
DOI:10.1016/j.bmcl.2011.06.117