Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation. Issue 13 (1st July 2020)

• Record Type: Journal Article
• Authors: Yu, Wensheng; Liu, Jian; Yu, Younong; Zhang, Vivian; Clausen, Dane; Kelly, Joseph; Wolkenberg, Scott; Beshore, Douglas; Duffy, Joseph L.; Chung, Christine C.; Myers, Robert W.; Klein, Daniel J.; Fells, James; Holloway, Kate; Wu, Jin; Wu, Guoxin; Howell, Bonnie J.; Barnard, Richard J.O.; Kozlowski, Joseph
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 13(2020)
• Publication Date: 2020-07-01
• Subjects: 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; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127197
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.