DISCOVERY, SYNTHESIS, AND BIOACTIVITY OF BIS(HETEROARYL)PIPERAZINES .1. A NOVEL CLASS OF NONNUCLEOSIDE HIV-1 REVERSE-TRANSCRIPTASE INHIBITORS

• Published in: Journal of medicinal chemistry Vol. 37; no. 7; pp. 999 - 1014
• Main Authors: ROMERO, DL, MORGE, RA, BILES, C, BERRIOSPENA, TN, MAY, PD, PALMER, JOHNSON, PD, SMITH, HW, BUSSO, M, TAN, CK, VOORMAN, RL, REUSSER, F, ALTHAUS, IW, DOWNEY, KM, SO, AG, RESNICK, L, TARPLEY, WG, ARISTOFF, PA
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 01.04.1994
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; NONNUCLEOSIDE INHIBITORS; AIDS-RELATED COMPLEX; PHASE-I TRIAL; IMMUNODEFICIENCY-VIRUS TYPE-1; HIGH-LEVEL RESISTANCE; ANTI-HIV-1 ACTIVITY; 2',3'-DIDEOXYINOSINE DDI; PLACEBO-CONTROLLED TRIAL; 4,5,6,7-TETRAHYDRO-5-METHYLIMIDAZO<4,5,1-JK><1,4>BENZODIAZEPIN-2(1H)-ONE TIBO DE; AZIDOTHYMIDINE AZT
• ISSN: 0022-2623
• DOI: 10.1021/jm00033a018

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.