Wyeth

American National Red Cross

David LeRoy Crandall

Hassan Mahmoud Elokdah

Scott Christian Mayer

Eric Gould Gundersen

Geraldine Ruth McFarlane

Thomas Joseph Commons

Eugene John Trybulski

David Zenan Li

Lee Dalton Jennings

Susan Christman Croce

Daniel Lawrence

Hassan Mahmound Elokdah

Natalia Gorlatova

Richard Page Woodworth

This invention provides PAI-1 inhibiting compounds of Formula I: wherein: R, R, R, and Rare each H, alkyl, alkanoyl, halo, OH, aryl optionally substituted with R, perfluoroalkyl, alkoxy, amino, alkylamino, dialkylamino, perfluoroalkoxy; Ris H, alkyl, perfluoroalkyl, aryl optionally substituted with R, alkanoyl, aroyl optionally substituted with R; Ris H, alkyl, alkylaryl, benzyl optionally substituted with R, alkanoyl, aroyl optionally substituted with R; Ris H, alkyl, alkylaryl, aryl optionally substituted with R; n is 0-6; A is COOH, or an acid mimic such as tetraazole, SOH, POH, tetronic acid, etc.; Ris H, alkyl, cycloalkyl, alkanoyl, halo, OH, perfluoroalkyl, alkoxy, amino, alkylamino, dialkylamino, perfluoroalkoxy; or a pharmaceutically acceptable salt thereof; as well as pharmaceutical compositions and methods of treatment using these compounds.

Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)

The present invention relates generally to substituted biphenyloxy acids (such as 4'-aryl-amido-biphenyl-4(3)-yloxy-acids and 4&#x2032;-aryl-amidomethyl-biphenyl-4(3)-yloxy-acids) and methods of using them, for example, as PAI-1 inhibitors.

Biphenyloxy-acids

This invention provides compounds of the formula: wherein: X is a chemical bond, &#x2014;CH&#x2014; or &#x2014;C(O)&#x2014;; Ris alkyl, cycloalkyl, &#x2014;CH-cycloalkyl, pyridinyl, &#x2014;CH-pyridinyl, phenyl or benzyl; Ris H, alkyl, cycloalkyl, &#x2014;CH-cycloalkyl, or perfluoroalkyl; Ris H, halo, alkyl, perfluoroalkyl, alkoxy, cycloalkyl, &#x2014;CH-cycloalkyl, &#x2014;NH, or &#x2014;NO; Ris optionally substituted phenyl, benzyl, benzyloxy, pyridinyl, or &#x2014;CH-pyridinyl, or the salt or ester forms thereof, as well as methods for using the compounds as inhibitors of plasminogen activator inhibitor-1 (PAI-1) and as therapeutic compositions for treating conditions resulting from fibrinolytic disorders such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis.

Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)

A library of mutants of metastable proteins, such as proteinase inhibitors, can be screened for the specific loss of a wild-type capability to bind an antibody, yielding valuable drug-design information which otherwise is unavailable. By this approach, for example, a mutant proteinase inhibitor can be obtained that has the amino acid sequence of a wild-type protein, or an active fragment thereof, save for the presence of one or more mutations in at least one epitope, thereby altering interaction of the mutant with an anti-proteinase inhibitor antibody.

Mutant proteinase-inhibitors and uses thereof

This invention provides compounds of the formula:wherein: X is a chemical bond, &#x2014;CH&#x2014; or &#x2014;C(O)&#x2014;; Ris alkyl, cycloalkyl, &#x2014;CH-cycloalkyl, pyridinyl, &#x2014;CH-pyridinyl, phenyl or benzyl; Ris H, alkyl, cycloalkyl, &#x2014;CH-cycloalkyl, or perfluoroalkyl; Ris H, halo, alkyl, perfluoroalkyl, alkoxy, cycloalkyl, &#x2014;CH-cycloalkyl, &#x2014;NH, or &#x2014;NO; Ris optionally substituted phenyl, benzyl, benzyloxy, pyridinyl, or &#x2014;CH-pyridinyl, or the salt or ester forms thereof, as well as methods for using the compounds as inhibitors of plasminogen activator inhibitor-1 (PAI-1) and as therapeutic compositions for treating conditions resulting from fibrinolytic disorders such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis.

This invention provides PAI-1 inhibiting compounds of Formula I:wherein: R, R, R, and Rare each H, alkyl, alkanoyl, halo, OH, aryl optionally substituted with R, perfluoroalkyl, alkoxy, amino, alkylamino, dialkylamino, perfluoroalkoxy; Ris H, alkyl, perfluoroalkyl, aryl optionally substituted with R, alkanoyl, aroyl optionally substituted with R; Ris H, alkyl, alkylaryl, benzyl optionally substituted with R, alkanoyl, aroyl optionally substituted with R; Ris H, alkyl, alkylaryl, aryl optionally substituted with R; n is 0-6; A is COOH, or an acid mimic such as tetraazole, SOH, POH, tetronic acid, etc.; Ris H, alkyl, cycloalkyl, alkanoyl, halo, OH, perfluoroalkyl, alkoxy, amino, alkylamino, dialkylamino, perfluoroalkoxy; or a pharmaceutically acceptable salt thereof; as well as pharmaceutical compositions and methods of treatment using these compounds.

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Doylestown, PA, United States of America

David LeRoy Crandall