title: Discovery, synthesis, and bioactivity of bis(heteroaryl)piperazines. 1. A novel class of non-nucleoside HIV-1 reverse transcriptase inhibitors.
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.
authors.affiliation: Upjohn Laboratories, Kalamazoo, Michigan 49001.
authors.forename: D L
authors.initials: DL
authors.lastname: Romero
authors.forename: R A
authors.initials: RA
authors.lastname: Morge
authors.forename: C
authors.initials: C
authors.lastname: Biles
authors.forename: N
authors.initials: N
authors.lastname: Berrios-Pena
authors.forename: P D
authors.initials: PD
authors.lastname: May
authors.forename: J R
authors.initials: JR
authors.lastname: Palmer
authors.forename: P D
authors.initials: PD
authors.lastname: Johnson
authors.forename: H W
authors.initials: HW
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Busso
authors.forename: C K
authors.initials: CK
authors.lastname: Tan
mesh_terms: 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
chemical_list: 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