title: Design and Synthesis of Orally Bioavailable 4-Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors.
abstract: 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), cocrystal 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 demonstrated high oral bioavailability and liver exposure and achieved over 2 log viral load reduction in a hydrodynamic injected (HDI) HBV mouse model.
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Zongxing
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Lin
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Wenming
authors.initials: W
authors.lastname: Chen
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Weixing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Liu
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Guolong
authors.initials: G
authors.lastname: Wu
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Mengwei
authors.initials: M
authors.lastname: Huang
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Ning
authors.initials: N
authors.lastname: Qin
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ren
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Wu
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Liping
authors.initials: L
authors.lastname: Shi
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Fang
authors.initials: F
authors.lastname: Shen
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Wengang
authors.initials: W
authors.lastname: Yang
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Jim Z
authors.initials: JZ
authors.lastname: Wu
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Mayweg
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Hong C
authors.initials: HC
authors.lastname: Shen
authors.affiliation: Roche Innovation Center Shanghai, ‡Medicinal Chemistry, §Chemical Biology, ∥Pharmaceutical Sciences, and ⊥Discovery Virology, Roche Pharma Research and Early Development , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Tang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002213:Capsid / Q000378:metabolism*; D004195:Disease Models, Animal; D015195:Drug Design; D005260:Female; D006515:Hepatitis B virus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011743:Pyrimidines