Design and synthesis of phenylisoxazole derivatives as novel human acrosin inhibitors |
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| Institution: | 1. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi ‘Aldo Moro’ di Bari, Via Orabona 4, 70126 Bari, Italy;2. Università degli Studi di Firenze, Dipartimento di Chimica, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy;3. Università degli Studi di Firenze, Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, Via U. Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy;1. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan;2. Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka 1000, Bangladesh;3. Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh;1. Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, A-1090, Vienna, Austria;2. Department of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, H?gyes Endre u. 7, H-1092, Budapest, Hungary;1. Lab of Immunoregulation, DVP, Office of Vaccines, Center for Biologics, FDA, Bldg 72, Room 1212, White Oak Campus, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA;2. Human Retrovirus Pathogenesis Section, NCI Frederick, Bldg 535, Room 209, Frederick, MD 21702, USA;3. Department of Immunology and Microbial Science, IAVI Neutralizing Antibody Center and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA;1. Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;2. Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China;3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China;4. Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China |
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| Abstract: | 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. |
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| Keywords: | Guanidinophenylpyrazole derivatives Molecular hybridization Male contraceptive Human acrosin inhibitors |
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