title: Discovery of a novel A2B adenosine receptor antagonist as a clinical candidate for chronic inflammatory airway diseases.
abstract: Recently, we have reported a series of new 1,3-symmetrically (R 1 = R 3) substituted xanthines ( 3 and 4) which have high affinity and selectivity for the human adenosine A 2B receptors (hA(2B)-AdoR). Unfortunately, this class of compounds had poor pharmacokinetic properties. This prompted us to investigate the effect of differential alkyl substitution at the N-1 and N-3 positions ( N 1-R not equal to N 3-R) on A(2B)-AdoR affinity and selectivity; we had the dual objectives of enhancing affinity and selectivity for the A(2B)-AdoR, as well as improving oral bioavailability. This effort has led to the discovery of compound 62, that displayed high affinity and selectivity for the hA(2B)-AdoR (K(i) = 22 nM). In addition, compound 62 showed high functional potency in inhibiting the accumulation of cyclic adenosine monophosphate induced by 5'- N-ethylcarboxamidoadenosine in HEK-A(2B)-AdoR and NIH3T3 cells with K(B) values of 6 and 2 nM, respectively. In a single ascending-dose phase I clinical study, compound 62 had no serious adverse events and was well tolerated.
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 V
authors.initials: RV
authors.lastname: Kalla
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.forename: Thao
authors.initials: T
authors.lastname: Perry
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; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D000242:Cyclic AMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D014970:Xanthines; D000242:Cyclic AMP