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Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation
Institution:1. Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA;1. Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam;2. College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk 28160, Republic of Korea;3. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk, Republic of Korea;4. Faculty of Pharmacy, PHENIKAA University, Hanoi 12116, Viet Nam;5. PHENIKAA Institute for Advanced Study (PIAS), PHENIKAA University, Hanoi 12116, Viet Nam;1. Department of Medicine, Mackay Medical College, New Taipei City, Taiwan;2. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan;3. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;4. Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taiwan;5. Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan;6. Division of Urology, Taipei City Hospital HepingFuyou Branch, Taipei, Taiwan;7. Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;1. School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan;2. Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan;3. Taipei Neuroscience Institute, Taipei Medical University, Taiwan;4. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institute, Zhunan Town, Miaoli County, Taiwan;5. TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan;1. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400 USA;2. School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332-0400 USA;3. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400 USA;4. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332-0400 USA
Abstract:A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well.
Keywords:HDAC inhibitor  HIV latency  Zinc binding group  Shock and kill  2C4 cells  HDACs 1  2  3  HDACs 6  8  HIV latency reversing agent  JBQVEFSGVBJRDX-XAADTVQCSA-N  OVCJVAPOZGLRMA-FNRXZAJISA-N  OVCJVAPOZGLRMA-ZTCGNLEXSA-N  BQXSWZISXQECGB-KQCWQIBISA-N  BQXSWZISXQECGB-SPEQKHQFSA-N  IQHPXZXAXOFZNT-UGTQYVAGSA-N  IQHPXZXAXOFZNT-PSDKUCRISA-N  ZLOLBXAMJIMWRO-DYDAFRNPSA-N  ZLOLBXAMJIMWRO-BIDFJRRLSA-N  BFWQSZQTJDASLR-IDSIGLAPSA-N  ZXJKASKUBGPESN-ARIMWLFLSA-N  AZPURTXNNXURJB-DFAZZDQMSA-N  ZXJKASKUBGPESN-VJTBXHKVSA-N  HDUMQCOVMCEYLI-MRUSTHFTSA-N  HDUMQCOVMCEYLI-SSZBAEQDSA-N  URTCBVWIWDGUBB-JUUFQDFKSA-N  CLRBQGFEGMQJBJ-DYDAFRNPSA-N  DWYCYNNQFGYCLX-DYDAFRNPSA-N  UPHPTYQREPLPPM-RAJQYVHUSA-N  SLBFJMGQZYFEBZ-JUUFQDFKSA-N  VXULGDOBJJEJBZ-SPEQKHQFSA-N  LYTLKUJDBRMNST-JUUFQDFKSA-N  WTZPQXWWWHBXMA-UPVQGACJSA-N  VVBKGYYWUVLDFO-DWWWOVOOSA-N  KWHOJYABKCNGKV-FUTGNJDKSA-N  OKMKERCNQLGIGI-CATFJDEUSA-N  PDAGJFRKYMOTFF-SPEQKHQFSA-N  YRUYUOONQJFOJS-JUUFQDFKSA-N  LIUSFHAPKJLQOE-DYDAFRNPSA-N  ASSPISHAFBMFBF-JUOQHSBGSA-N  OLIOPZKFXJWCDT-JUOQHSBGSA-N  MNMYAADXICACPL-SPEQKHQFSA-N  WTZPQXWWWHBXMA-VWNXMTODSA-N  ACZCWVKQNYAZBA-VWLOTQADSA-N  ICECJYVQJUQARO-SANMLTNESA-N  HHIRKUWNXWZRBC-MHZLTWQESA-N  FHNMOTPPVMNTJS-BWQBABIRSA-N  FHNMOTPPVMNTJS-FWVWFNHBSA-N
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