Design and synthesis of phenylisoxazole derivatives as novel human acrosin inhibitors.
Human acrosin is an attractive target for the discovery of novel male contraceptives. Isoxazole derivative ISO-1, a small-molecule weak human acrosin inhibitor, was used as the starting point for lead optimization. After two rounds of structure-based inhibitor design, a highly potent inhibitor B6 (IC50=1.44 μM) was successfully identified, which showed good selectivity over trypsin and represents one of the most active human acrosin inhibitors up to date.
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Juntao
J
Zhao
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Wei
W
Tian
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Jingjing
J
Qi
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Diya
D
Lv
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Yang
Y
Liu
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Yan
Y
Jiang
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Guoqiang
G
Dong
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Qianqian
Q
Chen
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Youjun
Y
Zhou
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Ju
J
Zhu
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Heling
H
Wang
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: shengcq@hotmail.com.
Chunquan
C
Sheng
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: ljg19580808@163.com.
Jiaguo
J
Lv
D000176:Acrosin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D007555:Isoxazoles; D000176:Acrosin
Guanidinophenylpyrazole derivatives; Human acrosin inhibitors; Male contraceptive; Molecular hybridization