Discovery of a Novel A2B Adenosine Receptor Antagonist as a Clinical Candidate for Chronic Inflammatory Airway Diseases

详细信息    查看全文

• 作者：Elfatih Elzein ; Rao V. Kalla ; Xiaofen Li ; Thao Perry ; Art Gimbel ; Dewan Zeng ; David Lustig ; Kwan Leung ; Jeff Zablocki
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 10, 2008
• 年：2008
• 卷：51
• 期：7
• 页码：2267 - 2278
• 全文大小：288K
• 年卷期：v.51,no.7(April 10, 2008)
• ISSN：1520-4804

文摘

Recently, we have reported a series of new 1,3-symmetrically (R₁ = R₃) 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 (N₁-R ≠ N₃-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.