Structure-based design of nonpeptidic HIV protease inhibitors: The sulfonamide-substituted cyclooctylpyranones

被引:88
作者
Skulnick, HI
Johnson, PD
Aristoff, PA
Morris, JK
Lovasz, KD
Howe, WJ
Watenpaugh, KD
Janakiraman, MN
Anderson, DJ
Reischer, RJ
Schwartz, TM
Banitt, LS
Tomich, PK
Lynn, JC
Horng, MM
Chong, KT
Hinshaw, RR
Dolak, LA
Seest, EP
Schwende, FJ
Rush, BD
Howard, GM
Toth, LN
Wilkinson, KR
Kakuk, TJ
Johnson, CW
Cole, SL
Zaya, RM
Zipp, GL
Possert, PL
Dalga, RJ
Zhong, WZ
Williams, MG
Romines, KR
机构
[1] PHARMACIA & UPJOHN INC,STRUCT ANALYT & MED CHEM RES,KALAMAZOO,MI 49001
[2] PHARMACIA & UPJOHN INC,DISCOVERY CHEM RES,KALAMAZOO,MI 49001
[3] PHARMACIA & UPJOHN INC,COMP ASSISTED DRUG DESIGN,KALAMAZOO,MI 49001
[4] PHARMACIA & UPJOHN INC,MED CHEM RES,KALAMAZOO,MI 49001
[5] PHARMACIA & UPJOHN INC,CHEM & BIOL SCREENING,KALAMAZOO,MI 49001
[6] PHARMACIA & UPJOHN INC,INFECT DIS RES,KALAMAZOO,MI 49001
[7] PHARMACIA & UPJOHN INC,DRUG METAB RES,KALAMAZOO,MI 49001
[8] PHARMACIA & UPJOHN INC,TOXICOL,KALAMAZOO,MI 49001
[9] PHARMACIA & UPJOHN INC,PHARMACEUT DEV,KALAMAZOO,MI 49001
关键词
AIDS; 4-HYDROXY-2-PYRONES; 4-HYDROXYCOUMARINS;
D O I
10.1021/jm960441m
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.
引用
收藏
页码:1149 / 1164
页数:16
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