Discovery, synthesis, and bioactivity of bis(heteroaryl)piperazines. 1. A novel class of non-nucleoside HIV-1 reverse transcriptase inhibitors.
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.
Romero
D L
DL
Upjohn Laboratories, Kalamazoo, Michigan 49001.
Morge
R A
RA
Biles
C
C
Berrios-Pena
N
N
May
P D
PD
Palmer
J R
JR
Johnson
P D
PD
Smith
H W
HW
Busso
M
M
Tan
C K
CK
D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors
D000631:Aminopyridines; D000998:Antiviral Agents; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; C086719:1-(4-methoxy-3,5-dimethylbenzyl)-4-(3-(ethylamino)-2-pyridyl)piperazine hydrochloride; D054303:HIV Reverse Transcriptase; C076632:atevirdine