Discovery and Pre-Clinical Characterization of Third-Generation 4-H Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors.
Described herein are the discovery and structure-activity relationship (SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring the introduction of a C6 carboxyl group as novel HBV capsid inhibitors. This new series of 4-H HAPs showed improved anti-HBV activity and better drug-like properties compared to the first- and second-generation 4-H HAPs. X-ray crystallographic study of analogue 12 (HAP_R01) with Cp149 Y132A mutant hexamer clearly elucidated the role of C6 carboxyl group played for the increased binding affinity, which formed strong hydrogen bonding interactions with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET) and in vivo (mouse PK and PD) and subsequently selected for further development as oral anti-HBV infection agent.
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Zongxing
Z
Qiu
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Xianfeng
X
Lin
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Weixing
W
Zhang
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Mingwei
M
Zhou
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Lei
L
Guo
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Buelent
B
Kocer
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Guolong
G
Wu
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Zhisen
Z
Zhang
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Haixia
H
Liu
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Houguang
H
Shi
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Buyu
B
Kou
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Taishan
T
Hu
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Yimin
Y
Hu
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Mengwei
M
Huang
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
S Frank
SF
Yan
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Zhiheng
Z
Xu
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Zheng
Z
Zhou
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Ning
N
Qin
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Yue Fen
YF
Wang
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Shuang
S
Ren
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Hongxia
H
Qiu
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Yuxia
Y
Zhang
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Yi
Y
Zhang
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Xiaoyue
X
Wu
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Kai
K
Sun
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Sheng
S
Zhong
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Jianxun
J
Xie
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Giorgio
G
Ottaviani
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Yuan
Y
Zhou
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Lina
L
Zhu
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Xiaojun
X
Tian
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Liping
L
Shi
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Fang
F
Shen
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Yi
Y
Mao
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Xue
X
Zhou
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Lu
L
Gao
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
John A T
JAT
Young
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Jim Zhen
JZ
Wu
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Guang
G
Yang
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Alexander V
AV
Mayweg
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Hong C
HC
Shen
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Guozhi
0000-0002-7131-4678
G
Tang
Roche Innovation Center Shanghai, ‡Roche Innovation Center Basel, §Medicinal Chemistry, ∥Chemical Biology, ⊥Pharmaceutical Sciences, #Discovery Virology, Roche Pharma Research and Early Development , Bldg 5, 720 Cailun Road, Shanghai 201203, China.
Wei
0000-0003-4701-2474
W
Zhu
D000818:Animals; D002213:Capsid / Q000187:drug effects*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D066244:Proton Magnetic Resonance Spectroscopy; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011743:Pyrimidines