Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy

被引：177

作者：

Kempf, DJ ^{[1
]}

Sham, HL ^{[1
]}

Marsh, KC ^{[1
]}

Flentge, CA ^{[1
]}

Betebenner, D ^{[1
]}

Green, BE ^{[1
]}

McDonald, E ^{[1
]}

Vasavanonda, S ^{[1
]}

Saldivar, A ^{[1
]}

Wideburg, NE ^{[1
]}

Kati, WM ^{[1
]}

Ruiz, L ^{[1
]}

Zhao, C ^{[1
]}

Fino, LM ^{[1
]}

Patterson, J ^{[1
]}

Molla, A ^{[1
]}

Plattner, JJ ^{[1
]}

Norbeck, DW ^{[1
]}

机构：

[1] Abbott Labs, Div Pharmaceut Prod, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 04期

关键词：

D O I：

10.1021/jm970636+

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption, Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 mu M) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.

引用

页码：602 / 617

页数：16

共 56 条

[1] REDUCTION OF THE IN-VITRO ACTIVITY OF A77003, AN INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASE, BY HUMAN SERUM ALPHA(1) ACID GLYCOPROTEIN [J].

BILELLO, JA ;

BILELLO, PA ;

PRICHARD, M ;

ROBINS, T ;

DRUSANO, GL .

JOURNAL OF INFECTIOUS DISEASES, 1995, 171 (03) :546-551

[2]

Clare Michael, 1993, Perspectives in Drug Discovery and Design, V1, P49, DOI 10.1007/BF02171655

[3]

COHEN C, 1996, 36 INT C ANT AG CHEM

[4] A SHORT-TERM STUDY OF THE SAFETY, PHARMACOKINETICS, AND EFFICACY OF RITONAVIR, AN INHIBITOR OF HIV-1 PROTEASE [J].

DANNER, SA ;

CARR, A ;

LEONARD, JM ;

LEHMAN, LM ;

GUDIOL, F ;

GONZALES, J ;

RAVENTOS, A ;

RUBIO, R ;

BOUZA, E ;

PINTADO, V ;

AGUADO, AG ;

DELOMAS, JG ;

DELGADO, R ;

BORLEFFS, JCC ;

HSU, A ;

VALDES, JM ;

BOUCHER, CAB ;

COOPER, DA ;

GIMENO, C ;

CLOTET, B ;

TOR, J ;

FERRER, E ;

MARTINEZ, PL ;

MORENO, S ;

ZANCADA, G ;

ALCAMI, J ;

NORIEGA, AR ;

PULIDO, F ;

GLASSMAN, HN .

NEW ENGLAND JOURNAL OF MEDICINE, 1995, 333 (23) :1528-1533

[5]

Darke P L, 1994, Adv Pharmacol, V25, P399, DOI 10.1016/S1054-3589(08)60438-X

[6] HIV-1 PROTEASE SPECIFICITY OF PEPTIDE CLEAVAGE IS SUFFICIENT FOR PROCESSING OF GAG AND POL POLYPROTEINS [J].

DARKE, PL ;

NUTT, RF ;

BRADY, SF ;

GARSKY, VM ;

CICCARONE, TM ;

LEU, CT ;

LUMMA, PK ;

FREIDINGER, RM ;

VEBER, DF ;

SIGAL, IS .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1988, 156 (01) :297-303

[7] HUMAN IMMUNODEFICIENCY VIRUS PROTEASE EXPRESSED IN ESCHERICHIA-COLI EXHIBITS AUTOPROCESSING AND SPECIFIC MATURATION OF THE GAG PRECURSOR [J].

DEBOUCK, C ;

GORNIAK, JG ;

STRICKLER, JE ;

MEEK, TD ;

METCALF, BW ;

ROSENBERG, M .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (24) :8903-8906

[8]

Denissen Jon F., 1993, Pharmaceutical Research (New York), V10, pS376

[9] L-735,524 - THE DESIGN OF A POTENT AND ORALLY BIOAVAILABLE HIV PROTEASE INHIBITOR [J].

DORSEY, BD ;

LEVIN, RB ;

MCDANIEL, SL ;

VACCA, JP ;

GUARE, JP ;

DARKE, PL ;

ZUGAY, JA ;

EMINI, EA ;

SCHLEIF, WA ;

QUINTERO, JC ;

LIN, JH ;

CHEN, IW ;

HOLLOWAY, MK ;

FITZGERALD, PMD ;

AXEL, MG ;

OSTOVIC, D ;

ANDERSON, PS ;

HUFF, JR .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (21) :3443-3451

[10]

ERICKSON J, 1994, ARCH VIROL, P19

← 1 2 3 4 5 6 →