Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X7 receptor.
Bioorg Med Chem Lett
; 21(18): 5475-9, 2011 Sep 15.
Article
in En
| MEDLINE
| ID: mdl-21782426
ABSTRACT
The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X(7) receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd(ss). 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(ss) of 39 via introduction of amines led to analogs 40 and 41 which maintained the favorable pharmacology profile of 39 and improved Vd(ss) after iv dosing. But these analogs suffered from poor oral absorption, probably driven by poor permeability.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Benzamides
/
Drug Discovery
/
Receptors, Purinergic P2X7
/
Purinergic P2X Receptor Antagonists
Limits:
Animals
/
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2011
Type:
Article
Affiliation country:
United States