Discovery of piperidine-substituted thiazolo[5,4-d]pyrimidine derivatives as potent and orally bioavailable HIV-1 non-nucleoside reverse transcriptase inhibitors

• DOI: 10.1038/s42004-019-0174-8
• Publication Date: 2019-06-28T10:03:14Z
• Authors: Dongwei Kang; Tong Zhao; Zhao Wang; Da Feng; Heng Zhang; Boshi Huang; Gaochan Wu; Fenju Wei; Zhongxia Zhou; Lanlan Jing; Xiaofang Zuo; Ye Tian; Vasanthanathan Po...; Jacob Kongsted; Erik De Clercq; Christophe Pannec...; Peng Zhan; Xinyong Liu
• Keywords: DRUG-RESISTANCE; 0301 basic medicine; Chemistry; 03 medical and health sciences; Science & Technology; DESIGN; IMPACT; Chemistry, Multidisciplinary; Physical Sciences; METABOLISM; LIPOPHILIC EFFICIENCY; 3. Good health

AbstractHIV-1 reverse transcriptase offers a key target for antiviral therapy. However, the rapid emergence of drug-resistant mutations in reverse transcriptase as well as the poor pharmacokinetic properties of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) limits their clinical use. Starting from a previous piperidine-substituted thiophene[3,2-d]pyrimidine compound (K-5a2), here we explore the chemical space around the thiophene ring located in the solvent-exposed regions of the NNRTI binding pocket in detail. Bioisosterism-based structural modification leads to the discovery of a number of compounds as potent in vitro reverse transcriptase inhibitors, providing improved drug resistance profiles compared to the listed drug Etravirine. Furthermore, 14a and 19a are identified as lead compounds with good solubility, appropriate ligand efficiency, and lower cytochrome P450 liability. Compound 19a exhibits useful in vivo pharmacokinetic properties in rat and safety in mice, suggesting that it may have the potential to be an effective drug candidate for treating AIDS.