Drug-like property-driven optimization of 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against rilpivirine-resistant mutant virus

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Wei, Lei¹  Wang, Hui-Ling¹  Huang, Li²  Chen, Chin-Ho²  Morris-Natschke, Susan L.³  Lee, Kuo-Hsiung^3,4  Xie, Lan^1,3 

[1] Beijing Inst Pharmacol & Toxicol, 27 Tai Ping Rd, Beijing 100850, Peoples R China

[2] Duke Univ, Med Ctr, Surg Oncol Res Facil, Box 2926, Durham, NC 27710 USA

[3] Univ N Carolina, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA

[4] China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung, Taiwan

关键词: HIV-1 NNRTIs;    Diarylaniline;    Drug-like property;    Anti-resistance;   

DOI  :  10.1016/j.bmcl.2017.04.068

来源: Elsevier

【 摘 要 】

On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R-1) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a-8g) with different R-1 side chains plus prior active p-cyanoethyl-DAANs (4a-4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma. This study revealed that both ester and amide R-1 substituents led to low nanomolar anti-HIV potency against wild-type and rilpivirine-resistant viral strains (E138K-resistance fold changes < 3). The N-substituted amide-R-1 side chains were superior to ester-R-1 likely due to improved aqueous solubility, lipophilicity, and higher metabolic stability in vitro. Thus, three amide-DAANs 8e, 4a, and 4b were identified with high potency against wild-type and rilpivirine-resistant viral strains and multiple desirable drug-like properties. (C) 2017 Elsevier Ltd. All rights reserved.

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