- Cycloalkylpyranones and cycloalkyldihydropyrones as HIV protease inhibitors: Exploring the impact of ring size on structure-activity relationships
-
Previously, 3-substituted cycloalkylpyranones, such as 2d, have proven to be effective inhibitors of HIV protease. In an initial series of 3-(1- phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We be
- Romines, Karen R.,Morris, Jeanette K.,Howe, W. Jeffrey,Tomich, Paul K.,Horng, Miao-Miao,Chong, Kong-Teck,Hinshaw, Roger R.,Anderson, David J.,Strohbach, Joseph W.,Turner, Steve-R.,Mizsak, Steve A.
-
-
Read Online
- SULFONYL PYRIDYL TRP INHIBITORS
-
The invention is concerned with the compounds of formula I: (I) and pharmaceutically acceptable salts thereof where R1 is a substituted or unsubstituted phenyl or a fused bicyclic comprising a substituted or unsubstituted phenyl. In addition, t
- -
-
Paragraph 0290-0291
(2018/03/06)
-
- Structure-based design of nonpeptidic HIV protease inhibitors: The sulfonamide-substituted cyelooctylpyranones
-
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.
- Skulnick, Harvey I.,Johnson, Paul D.,Aristoff, Paul A.,Morris, Jeanette K.,Lovasz, Kristine D.,Howe, W. Jeffrey,Watenpaugh, Keith D.,Janakiraman, Musiri N.,Anderson, David J.,Reischer, Robert J.,Schwartz, Theresa M.,Banitt, Lee S.,Tomich, Paul K.,Lynn, Janet C.,Horng, Miao-Miao,Chong, Kong-Teck,Hinshaw, Roger R.,Dolak, Lester A.,Seest, Eric P.,Schwende, Francis J.,Rush, Bob D.,Howard, Gina M.,Toth, Lisa N.,Wilkinson, Karen R.,Kakuk, Thomas J.,Johnson, Carol W.,Cole, Serena L.,Zaya, Renee M.,Zipp, Gail L.,Possert, Peggy L.,Dalga, Robert J.,Zhong, Wei-Zhu,Williams, Marta G.,Romines, Karen R.
-
p. 1149 - 1164
(2007/10/03)
-
