title: Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X₇ receptor.
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.
authors.affiliation: Neuroscience Chemistry, Pfizer Global R&D, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. Chakrapani.Subramanyam@pfizer.com
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Duplantier
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dombroski
authors.forename: Shang-Poa
authors.initials: SP
authors.lastname: Chang
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Gabel
authors.forename: Carrie
authors.initials: C
authors.lastname: Whitney-Pickett
authors.forename: David G
authors.initials: DG
authors.lastname: Perregaux
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Labasi
authors.forename: Kwansik
authors.initials: K
authors.lastname: Yoon
authors.forename: Richard M
authors.initials: RM
authors.lastname: Shepard
authors.forename: Michael
authors.initials: M
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D058920:Purinergic P2X Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7