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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.

Publication ,  Journal Article
Wei, L; Wang, H-L; Huang, L; Chen, C-H; Morris-Natschke, SL; Lee, K-H; Xie, L
Published in: Bioorg Med Chem Lett
June 15, 2017

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 (R1) 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 R1 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 R1 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-R1 side chains were superior to ester-R1 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.

Duke Scholars

Published In

Bioorg Med Chem Lett

DOI

EISSN

1464-3405

Publication Date

June 15, 2017

Volume

27

Issue

12

Start / End Page

2788 / 2792

Location

England

Related Subject Headings

  • Virus Replication
  • Structure-Activity Relationship
  • Rilpivirine
  • Reverse Transcriptase Inhibitors
  • Mutation
  • Molecular Structure
  • Microbial Sensitivity Tests
  • Medicinal & Biomolecular Chemistry
  • HIV-1
  • HIV Reverse Transcriptase
 

Citation

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Wei, L., Wang, H.-L., Huang, L., Chen, C.-H., Morris-Natschke, S. L., Lee, K.-H., & Xie, L. (2017). 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. Bioorg Med Chem Lett, 27(12), 2788–2792. https://doi.org/10.1016/j.bmcl.2017.04.068
Wei, Lei, Hui-Ling Wang, Li Huang, Chin-Ho Chen, Susan L. Morris-Natschke, Kuo-Hsiung Lee, and Lan Xie. “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.Bioorg Med Chem Lett 27, no. 12 (June 15, 2017): 2788–92. https://doi.org/10.1016/j.bmcl.2017.04.068.
Wei L, Wang H-L, Huang L, Chen C-H, Morris-Natschke SL, Lee K-H, et al. 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. Bioorg Med Chem Lett. 2017 Jun 15;27(12):2788–92.
Wei, Lei, et al. “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.Bioorg Med Chem Lett, vol. 27, no. 12, June 2017, pp. 2788–92. Pubmed, doi:10.1016/j.bmcl.2017.04.068.
Wei L, Wang H-L, Huang L, Chen C-H, Morris-Natschke SL, Lee K-H, Xie L. 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. Bioorg Med Chem Lett. 2017 Jun 15;27(12):2788–2792.
Journal cover image

Published In

Bioorg Med Chem Lett

DOI

EISSN

1464-3405

Publication Date

June 15, 2017

Volume

27

Issue

12

Start / End Page

2788 / 2792

Location

England

Related Subject Headings

  • Virus Replication
  • Structure-Activity Relationship
  • Rilpivirine
  • Reverse Transcriptase Inhibitors
  • Mutation
  • Molecular Structure
  • Microbial Sensitivity Tests
  • Medicinal & Biomolecular Chemistry
  • HIV-1
  • HIV Reverse Transcriptase