Cyclic HIV protease inhibitors:: Design and synthesis of orally bioavailable, pyrazole P2/P2′ cyclic ureas with improved potency

被引：68

作者：

Han, Q ^{[1
]}

Chang, CH ^{[1
]}

Li, RH ^{[1
]}

Ru, Y ^{[1
]}

Jadhav, PK ^{[1
]}

Lam, PYS ^{[1
]}

机构：

[1] Dupont Merck Pharmaceut Co, Expt Stn, Wilmington, DE 19880 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 12期

关键词：

D O I：

10.1021/jm9704199

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Highly potent HIV-1 protease (HIVPR) inhibitors have been designed and synthesized by introducing bidentate hydrogen-bonding oxime and pyrazole groups at the mete-position of the phenyl ring on the P2/P2' substituents of cyclic ureas. Nonsymmetrical cyclic ureas incorporating 3(1H)-pyrazolylbenzyl as P2 and hydrophilic functionalities as P2' show potent protease inhibition and antiviral activities against HIV and have good oral bioavailabilities. The X-ray structure of HTVPR.10A complex confirms that the two pyrazole rings of 10A form bidentate hydrogen bonds with the side-chain oxygen (C=O) and backbone nitrogen (N-H) of Asp30/30' of HIVPR.

引用

页码：2019 / 2028

页数：10

共 33 条

[1]

Appelt Krzysztof, 1993, Perspectives in Drug Discovery and Design, V1, P23, DOI 10.1007/BF02171654

[2] AN ASSAY FOR HIV RNA IN INFECTED CELL LYSATES, AND ITS USE FOR THE RAPID EVALUATION OF ANTIVIRAL EFFICACY [J].

BACHELER, LT ;

PAUL, M ;

OTTO, MJ ;

JADHAV, PK ;

STONE, BA ;

MILLER, JA .

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1994, 5 (02) :111-121

[3] CRYSTALLOGRAPHIC R-FACTOR REFINEMENT BY MOLECULAR-DYNAMICS [J].

BRUNGER, AT ;

KURIYAN, J ;

KARPLUS, M .

SCIENCE, 1987, 235 (4787) :458-460

[4]

Chang C. H., UNPUB

[5] IN-VIVO EMERGENCE OF HIV-1 VARIANTS RESISTANT TO MULTIPLE PROTEASE INHIBITORS [J].

CONDRA, JH ;

SCHLEIF, WA ;

BLAHY, OM ;

GABRYELSKI, LJ ;

GRAHAM, DJ ;

QUINTERO, JC ;

RHODES, A ;

ROBBINS, HL ;

ROTH, E ;

SHIVAPRAKASH, M ;

TITUS, D ;

YANG, T ;

TEPPLER, H ;

SQUIRES, KE ;

DEUTSCH, PJ ;

EMINI, EA .

NATURE, 1995, 374 (6522) :569-571

[6] THE HIV-1 PROTEASE AS A THERAPEUTIC TARGET FOR AIDS [J].

DEBOUCK, C .

AIDS RESEARCH AND HUMAN RETROVIRUSES, 1992, 8 (02) :153-164

[7] Cyclic HIV protease inhibitors capable of displacing the active site structural water molecule [J].

DeLucca, GV ;

EricksonViitanen, S ;

Lam, PYS .

DRUG DISCOVERY TODAY, 1997, 2 (01) :6-18

[8] DESIGN, ACTIVITY, AND 2.8 A CRYSTAL-STRUCTURE OF A C2 SYMMETRICAL INHIBITOR COMPLEXED TO HIV-1 PROTEASE [J].

ERICKSON, J ;

NEIDHART, DJ ;

VANDRIE, J ;

KEMPF, DJ ;

WANG, XC ;

NORBECK, DW ;

PLATTNER, JJ ;

RITTENHOUSE, JW ;

TURON, M ;

WIDEBURG, N ;

KOHLBRENNER, WE ;

SIMMER, R ;

HELFRICH, R ;

PAUL, DA ;

KNIGGE, M .

SCIENCE, 1990, 249 (4968) :527-533

[9] POTENCY AND SELECTIVITY OF INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASE BY A SMALL NONPEPTIDE C4 CYCLIC UREA, DMP-323 [J].

ERICKSONVIITANEN, S ;

KLABE, RM ;

CAWOOD, PG ;

ONEAL, PL ;

MEEK, JL .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1994, 38 (07) :1628-1634

[10] EVALUATION OF PHYSICOCHEMICAL PARAMETERS IMPORTANT TO THE ORAL BIOAVAILABILITY OF PEPTIDE-LIKE COMPOUNDS - IMPLICATIONS FOR THE SYNTHESIS OF RENIN INHIBITORS [J].

HAMILTON, HW ;

STEINBAUGH, BA ;

STEWART, BH ;

CHAN, OH ;

SCHMID, HL ;

SCHROEDER, R ;

RYAN, MJ ;

KEISER, J ;

TAYLOR, MD ;

BLANKLEY, CJ ;

KALTENBRONN, JS ;

WRIGHT, J ;

HICKS, J .

JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (09) :1446-1455

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