title: Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists.
abstract: A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A(2B)-AdoR antagonists have been synthesized and evaluated for their binding affinities for the A(2B), A(1), A(2A), and A(3)-AdoRs. 8-(1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (K(i)=1 nM) and selectivity for the A(2B)-AdoR versus A(1), A(2A), and A(3)-AdoRs (A(1)/A(2B), A(2A)/A(2B), and A(3)/A(2B) selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.
authors.affiliation: Department of Bioorganic Chemistry, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA. elfatih.elzein@cvt.com
authors.forename: Elfatih
authors.initials: E
authors.lastname: Elzein
authors.forename: Rao
authors.initials: R
authors.lastname: Kalla
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.forename: Thao
authors.initials: T
authors.lastname: Perry
authors.forename: Eric
authors.initials: E
authors.lastname: Parkhill
authors.forename: Venkata
authors.initials: V
authors.lastname: Palle
authors.forename: Vaibahv
authors.initials: V
authors.lastname: Varkhedkar
authors.forename: Art
authors.initials: A
authors.lastname: Gimbel
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: David
authors.initials: D
authors.lastname: Lustig
authors.forename: Kwan
authors.initials: K
authors.lastname: Leung
authors.forename: Jeff
authors.initials: J
authors.lastname: Zablocki
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011720:Pyrazoles; D014970:Xanthines