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

D L Romero; 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

doi:10.1021/jm00033a018

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.

Authors

D L Romero¹, 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, et al.

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.

MeSH terms

Aminopyridines / chemistry
Aminopyridines / pharmacology
Antiviral Agents / chemical synthesis*
Antiviral Agents / pharmacology
Cells, Cultured
HIV Reverse Transcriptase
HIV-1 / enzymology*
Humans
Molecular Structure
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / pharmacology
Reverse Transcriptase Inhibitors*

Substances

Aminopyridines
Antiviral Agents
Piperazines
Reverse Transcriptase Inhibitors
1-(4-methoxy-3,5-dimethylbenzyl)-4-(3-(ethylamino)-2-pyridyl)piperazine hydrochloride
HIV Reverse Transcriptase
atevirdine