2. Academic Validation
  3. Discovery, synthesis, and bioactivity of bis(heteroaryl)piperazines. 1. A novel class of non-nucleoside HIV-1 reverse transcriptase inhibitors

Discovery, synthesis, and bioactivity of bis(heteroaryl)piperazines. 1. A novel class of non-nucleoside HIV-1 reverse transcriptase inhibitors

  • J Med Chem. 1994 Apr 1;37(7):999-1014. doi: 10.1021/jm00033a018.
D L Romero 1,  R A Morge,  C Biles,  N Berrios-Pena,  P D May,  J R Palmer,  P D Johnson,  H W Smith,  M Busso,  C K Tan
Affiliations

Affiliation

  • 1 Upjohn Laboratories, Kalamazoo, Michigan 49001.
PMID: 7512142 DOI: 10.1021/jm00033a018
Abstract

A variety of analogues of 1-[4-methoxy-3,5-dimethylbenzyl]-4-[3-(ethylamino)-2-pyridyl]piperazine hydrochloride (U-80493E) were synthesized and evaluated for their inhibition of human immunodeficiency virus type 1 (HIV-1) Reverse Transcriptase (RT). Replacement of the substituted aryl moiety with various substituted indoles provided bis(heteroaryl)piperazines (BHAPs) that were 10-100-fold more potent than U-80493E. The pyridyl portion of the lead molecule was found to be very sensitive to modifications. Extensive preclinical evaluations of several of these compounds led to the selection of 1-[(5-methoxyindol-2-yl)carbonyl]-4-[3-(ethylamino)-2- pyridyl]piperazine methanesulfonate (U-87201E, atevirdine mesylate) for clinical evaluation.

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