The United States of America, As Represented by the Secretary, Department of Health and Human Services

University of Illinois

Other

The Rockefeller University

Tibotec Pharmaceuticals Ltd.

Sequoia Pharmaceuticals, Inc.

Aaron Diamond Aids Research Center

Sergei V Gulnik

John W Erickson

Hiroaki Mitsuya

Arun K Ghosh

Michael Eissenstat

Abelardo Silva

Betty Yu

Arun E Ghosh

Martin Markowitz

Arun K Gosh

The present invention provides an assay for determining the biochemical fitness of a biochemical species in a mutant replicating biological entity relative to its predecessor. The present invention further provides a continuous fluorogenic assay for measuring the anti-HIV protease activity of protease inhibitor. The present invention also provides a method of administering a therapeutic compound that reduces the chances of the emergence of drug resistance in therapy. The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, a prodrug, a composition, or an ester thereof, wherein A is a group of formulas (A), (B), (C) or (D); R, R, R, Ror Ris H, or an optionally substituted and/or heteroatom-bearing alkyl, alkenyl, alkynyl, or cyclic group; Y and/or Z are CH, O, S, SO, SO, amino, amides, carbamates, ureas, or thiocarbonyl derivatives thereof, optionally substituted with an alkyl, alkenyl, or alkynyl group; n is from 1 to 5; X is a bond, an optionally substituted methylene or ethylene, an amino, O or S; Q is C(O), C(S), or SO; m is from 0 to 6; Ris OH, &#x2550;O (keto), NH, or alkylamino, including esters, amides, and salts thereof; and W is C(O), C(S), S(O), or SO. Optionally, Rand R, together with the N&#x2014;W bond of formula (I), comprise a macrocyclic ring. 

Fitness assay and associated methods

Disclosed is a method of treating human immunodeficiency virus (HIV) infection in an antiretroviral treatment-experienced mammal, which involves administering to the mammal an effective amount of a compound of the formula:  or a pharmaceutically acceptable salt, a prodrug, or an ester thereof, or a pharmaceutically acceptable composition of the compound, the salt, the prodrug, or the ester thereof, wherein A, X, Q, W, m, and R-Rare as defined herein.

Method of treating HIV infection

The present invention provides an assay for determining the biochemical fitness of a biochemical species in a mutant replicating biological entity relative to its predecessor. The present invention further provides a continuous fluorogenic assay for measuring the anti-HIV protease activity of protease inhibitor. The present invention also provides a method of administering a therapeutic compound that reduces the chances of the emergence of drug resistance in therapy. The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, a prodrug, a composition, or an ester thereof, wherein A is a group of formulas (A), (B), (C) or (D); R, R, R, Ror Ris H, or an optionally substituted and/or heteroatom-bearing alkyl, alkenyl, alkynyl, or cyclic group; Y and/or Z are CH, O, S, SO, SO, amino, amides, carbamates, ureas, or thiocarbonyl derivatives thereof, optionally substituted with an alkyl, alkenyl, or alkynyl group; n is from 1 to 5; X is a bond, an optionally substituted methylene or ethylene, an amino, O or S; Q is C(O), C(S), or SO; m is from 0 to 6; Ris OH, &#x2550;O (keto), NH, or alkylamino, including esters, amides, and salts thereof; and W is C(O), C(S), S(O), or SO. Optionally, Rand R, together with the N&#x2014;W bond of formula (I), comprises a macrocyclic ring.

The present invention concerns a further development and use of biological assays to determine the amount or concentration of an active ingredient present in a sample. The enzyme assay of the present invention determines the amount or concentration of protease inhibitors, including retroviral protease inhibitors such as HIV inhibitors.

Protease assay for therapeutic drug monitoring

Resistance-repellent and multidrug resistant retroviral protease inhibitors are provided. Pharmaceutical composition comprising such compounds, and methods of using such compounds to treat HIV infections in mammals, are also provided.

Resistance-repellent retroviral protease inhibitors

Growing community of inventors

Frederick, MD, United States of America

Sergei V Gulnik