National Institutes of Health, a Component of the US Dept. of Health & Human Services

The United States of America As Represented by the Department of Health

Tibotec Pharmaceuticals Ltd.

Sequoia Pharmaceuticals, Inc.

University of Illinois

Other

The United States of America As Represented by the Secretary of

The Rockefeller University

Conjuchem Biotechnologies Inc.

Aaron Diamond Aids Research Center

John W Erickson

Michael Eissenstat

Sergei V Gulnik

Ramnarayan S Randad

Hiroaki Mitsuya

Abelardo Silva

Arun K Ghosh

Dehui Duan

Dong Xie

Dominique P Bridon

Martin Robitaille

Guangyang Wang

Piet T B P Wigerinck

Lucyna Lubkowska

Grant A Krafft

Betty Yu

Talapadi N Bhat

Sergei Gulnik

Jack Collins

Pavel Majer

Martin Markowitz

Arun E Ghosh

Wei Cao

Sandra DeMeyer

Jun Liang

Elena Afonina

Sergi Gulnik

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

Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters to improve the pharmacokinetics, enhance the bioavailability, and enhance the therapeutic effect of drugs that undergo in vivo degradation by cytochrome P450 enzymes.

Methods for inhibiting drug degradation

Compositions and methods of treating viral infections are provided. More particularly, compositions including a combination of protease inhibitors and cytochrome p450 enzyme inhibitors are provided. Methods of using the compositions for treatment of diseases or disorders caused by a virus such as HIV infections are also provided.

HIV protease inhibitor and cytochrome p450 inhibitor combinations

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 relates to C34 peptide derivatives that are inhibitors of viral infection and/or exhibit antifusogenic properties. In particular, this invention relates to C34 derivatives having inhibiting activity against human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), human parainfluenza virus (HPV), measles virus (MeV), and simian immunodeficiency virus (SIV) with long duration of action for the treatment of the respective viral infections.

Long lasting fusion peptide inhibitors for 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

Compositions comprising bis-tetrahydrofuran benzodioxyolyl sulfonamide compounds that are surprisingly effective protease inhibitors and a second antiretroviral compound are disclosed. Methods of inhibiting retrovirus proteases, in particular multi-drug resistant retrovirus proteases, methods of treating or preventing infection or disease associated with retrovirus infection in a mammal, and methods of inhibiting viral replication are also disclosed.

Hexahydrofuro[2,3-B]furan-3-YL-N-{3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-benzyl-2-hydroxypropyl}carbamate as retroviral protease inhibitor

The invention provides compositions and methods that are useful for preventing and treating a coronavirus infection in a subject. More specifically, the invention provides peptides and conjugates and pharmaceutical compositions containing those peptides and conjugates that block fusion of a coronavirus, such as the SARS virus, to a target cell. This blocking mechanism prevents or treats a coronavirus infection, such as a SARS infection, in a subject, such as a human subject.

Antiviral agents for the treatment, control and prevention of infections by coronaviruses

The present invention provides an aspartic proteinase-inhibiting compound of the formula: wherein a, b, c, d, and e, can be the same or different and each are R, OR, SR, NRR, NHCOR, COR, CN, NO, NH, N, or a halogen, wherein Rand Rare independently H or an alkyl. Substituents Ror Rare each H or an alkyl. Substituent Ris a straight chain or branched alkyl, alkenyl, or alkynyl substituent, or is a cycloalkyl. Substituent A is OH, NH, or SH. Further provided are pharmaceutical compositions, which include a therapeutically effective amount of at least one of the foregoing compounds, and therapeutic methods of using the foregoing compounds.

Aspartic protease inhibitors

Methods for isothermal titration calorimetry analysis of the binding affinity of protease inhibitors to plasma proteins. A method that can quantitatively calculate free drug concentrations of protease inhibitors in human plasma, as well as a method to calculate therapeutic amounts and dosage regimens. Furthermore, the present invention provides a method that can calculate the effect of plasma proteins on the antiviral activity (EC50 values) of protease inhibitors from their binding affinities to plasma proteins. The present invention provides as well a method that can evaluate the in vivo anti-HIV efficacy of PIs in human plasma.

Methods for determining plasma free drug concentration by direct measurement of binding affinity of protease inhibitors to plasma proteins

Novel bis-tetrahydrofuran benzodioxolyl sulfonamide compounds which are surprisingly effective protease inhibitors. The invention also relates to pharmaceutical compositions, methods of inhibiting retrovirus proteases, in particular multidrug resistant retrovirus proteases, methods of treating or combating infection or disease associated with retrovirus infection in a mammal, and methods of inhibiting viral replication.

Hexahydrofuro&lsqb;2,3-B&rsqb;furan-3-yl-n&lcub;3&lsqb;(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino&rsqb;-1-benzyl-2-hydroxypropyl&rcub;carbamate as retroviral protease inhibitor

The present invention provides a compound of formula (I) wherein a, b, c, d, and e, are R , OR , SR , NR R , NHCOR , CO R , CN, NO , NH , N , or a halogen. R and R are H or alkyl, R and R are H or alkyl, and R is a non-aromatic substituent. Substituent A is OH, NH , or SH. Substituents B and B include amide and sulfonamide groups, which can be cyclic, acyclic, or amino acid derivatives. Alternatively, B and R&prime; together with the nitrogen to which they are bonded, and/or B&prime; and R together with the nitrogen to which they are bonded, define a heterocycle. The present invention further provides a pharmaceutical composition that includes a carrier and a therapeutically effective amount of at least one compound of the present invention. The present invention further provides therapeutic methods that include administering a therapeutically effective amount of at least one compound of the present invention

Growing community of inventors

Frederick, MD, United States of America

John W Erickson