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Publication Abstract from PubMed

Targeting the capsid protein of hepatitis B virus (HBV) and thus interrupting normal capsid formation have been an attractive approach to block the replication of HBV viruses. We carried out multidimensional structural optimizations based on the heteroaryldihydropyrimidine (HAP) analogue Bay41-4109 (1) and identified a novel series of HBV capsid inhibitors that demonstrated promising cellular selectivity indexes, metabolic stabilities, and in vitro safety profiles. Herein we disclose the design, synthesis, structure-activity relationship (SAR), co-crystal structure in complex with HBV capsid proteins, and in vivo pharmacological study of the 4-methyl HAP analogues. In particular, the (2S, 4S)-4,4-difluoroproline substituted analogue 34a demonstrate high oral bioavailability and liver exposure, and achieve > 2 log viral load reduction in a hydrodynamic injected (HDI) HBV mouse model.

Design and Synthesis of Orally Bioavailable 4-Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors.,Qiu Z, Lin X, Zhou M, Liu Y, Zhu W, Chen W, Zhang W, Guo L, Liu H, Wu G, Huang M, Jiang M, Xu Z, Zhou ZJ, Qin N, Ren S, Qiu H, Zhong S, Zhang Y, Zhang Y, Wu X, Shi L, Shen F, Mao Y, Zhou X, Yang W, Wu JZ, Yang G, Mayweg AV, Shen HC, Tang G J Med Chem. 2016 Jul 26. PMID:27458651^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.