Texas Biotechnology Corporation

Genentech, Inc.

Genetech, Inc.

Encysive Pharmaceuticals, Inc.

Timothy P Kogan

Chengde Wu

Karin M Keller

Bore G Raju

Natalie Blok

Avi J Ashkenazi

Steven M Chamow

Ian Leslie Scott

Pamela J Beck

Ming Fai Chan

Adam Kois

Erik Joel Verner

Vitukudi Narayanaiyengar Balaji

Patricia Woodard

Rosario Silvestre Castillo

Peter Vanderslice

Jamal M Kassir

Brian Dupre

Kaijun Ren

George W Holland

Ronald J Biediger

Robert V Market

Todd C Somers

Venkatachalapathi Yalamoori

Vanessa O Grabbe

Shuqun Lin

Huong Dao

Harold Meckler

Harold L Kohn

Huong Bui

Venkatachalapathi Yalamorri

Kathy L Wheeler

Ajay A Rege

Nam Huh

The present invention is directed to an isolated and purified cyclic peptide of from 5 to about 13 residues modeled after a portion of the CS1 peptide. A peptide of this invention preferably has the amino acid residue sequence of SEQ ID NO:2-14 or 16-42. The present invention is further directed to a process of selectively inhibiting the binding of &agr; &bgr; integrin to a protein such as VCAM-1, fibronectin or invasin. In accordance with that process, a cell that expresses &agr; &bgr; integrin is exposed to that protein in the presence of an effective inhibiting amount of such a peptide. The present invention is still further directed to a pharmaceutical composition containing a physiologically acceptable carrier and a cyclic peptide of the invention.

Process to inhibit binding of the integrin &agr;4&bgr;1 , to VCAM-1 fibronectin and cyclic peptides thereof

Thienylsulfonamides and their pharmaceutically acceptable derivatives, pharmaceutical compositions, articles of manufacture, combinations, lyophilized powders and methods for the treatment of endothelin diseases using these formulations and sulfonamides are provided. A process of preparing an alkali metal salt of a hydrophobic sulfonamide is provided. The process includes the step of dissolving a free sulfonamide in an organic solvent in the presence of a saturated alkali metal salt solution and recovering the formed sulfonamide salt from the organic phase.

Sulfonamides for treatment of endothelin-mediated disorders

Thienyl-, furyl- and pyrrolyl-sulfonamides, formulations of pharmaceutically-acceptable salts thereof and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)pyrrolylsulfonamides, formulations thereof and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit the activity of endothelin are also provided.

Sulfonamides and derivatives thereof that modulate the activity of endothelin

Biphenylsulfonamides and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, bicyclic or tricyclic carbon or heterocyclic ring biphenylsulfonamides and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.

Biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin

The invention provides heterobifunctional cross-linking reagents and methods of using the cross-linking reagents. The cross-linking reagents of the invention combine a nucleophilic hydrazide residue with an electrophilic maleimide residue allowing coupling of aldehydes to free thiols. In the methods of the invention, human immunodeficiency virus (HIV) infected cells can be detected using conjugates that include CD4 molecules conjugated to detectable markers via the disclosed cross-linking reagents.

Carbohydrate-directed cross-linking reagents

Formulations of pharmaceutically-acceptable salts of thienyl-, furyl- and pyrrolyl-sulfonamides and methods for modulating or altering the activity of the endothelin family of peptides using the formulations are provided. In particular, formulations of sodium salts of N-(isoxazolyl)-thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)-pyrrolylsulfonamides and methods using these sulfonamide salts for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide salt are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamide salts or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.

Formulation of sulfonamides for treatment of endothelin-mediated disorders

Thienyl-, furyl- and pyrrolyl-sulfonamides, pharmaceutically-acceptable salts of sulfonamides, formulations of salts and the sulfonamides, and methods for modulating or altering the activity of the endothelin family of peptides using the formulations and sulfonamides are provided. In particular, formulations of sodium salts of N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)pyrrolylsulfonamides are provided. A process of preparing an alkali metal salt of a hydrophobic sulfonamide is provided. The process includes the step of dissolving a free sulfonamide in an organic solvent in the presence of a saturated alkali metal salt solution and recovering the formed sulfonamide salt from the organic phase.

N-heteroaryl aryl-substituted thienyl-furyl-and pyrrolyl-sulfonamides and derviatives thereof that modulate the activity of endothelin

Thienyl-, furyl- and pyrrolyl-sulfonamides and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)pyrrolylsulfonamides and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.

N-aryl thienyl-, furyl-, and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin

N-alkyl, N-alkenyl, N-alkynyl, N-aryl and N-fused bicyclo or tricyclo thienyl-, furyl- and pyrrolyl-sulfonamides and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, (phenyl) and (phenoxy)thienylsulfonamides, (phenyl) and (phenoxy)furylsulfonamides, and (phenyl) and (phenoxy)pyrrolylsulfonamides and methods of using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.

N-Alkyl, N-Alkenyl, N-Alkynyl, N-Aryl and N-fused bicyclo or tricyclo thienyl-, furyl-,and Pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin

A method for the inhibition of the binding of &agr;,&bgr;,integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds that inhibit this binding; pharmaceutically active compositions thereof; and the use of the compounds either as above, or in formulations for the control or prevention of diseases states in which &agr;,&bgr;,is involved.

Compounds that inhibit the binding of integrins to their receptors

Formulations of pharmaceutically-acceptable salts of thienyl-, furyl- and pyrrolyl-sulfonamides and methods for modulating or altering the activity of the endothelin family of peptides using the formulations are provided. In particular, formulations of sodium salts of N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)pyrrolylsulfonamides and methods using these sulfonamide salts for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide salt are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamide salts or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.

A method for the inhibition of the binding of &agr;,&bgr;,integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds that inhibit this binding; pharmaceutically active compositions comprising such compounds; and the use of such compounds either as above, or in formulations for the control or prevention of diseases states in which &agr;,&bgr;,is involved.

N, N-disubstituted amides that inhibit the binding of integrins to their receptors

The invention provides heterobifunctional cross-linking reagents and methods of using the cross-linking reagents. The cross-linking reagents of the invention combine a nucleophilic hydrazide residue with an electrophilic maleimide residue, allowing coupling of aldehydes to free thiols. In the methods of the invention, human immunodeficiency virus (HIV) infected cells can be detected using conjugates that include CD4 molecules conjugated to detectable markers via the disclosed cross-linking reagents.

The present invention is directed to an isolated and purified cyclic peptide of from 5 to about 13 residues modeled after a portion of the CS1 peptide. A peptide of this invention preferably has the amino acid residue sequence of SEQ ID NO:2-14 or 16-42. The present invention is further directed to a process of selectively inhibiting the binding of .alpha..sub.4 .beta..sub.1 integrin to a protein such as VCAM-1, fibronectin or invasin. In accordance with that process, a cell that expresses .alpha..sub.4 .beta..sub.1 integrin is exposed to that protein in the presence of an effective inhibiting amount of such a peptide. The present invention is still further directed to a pharmaceutical composition containing a physiologically acceptable carrier and a cyclic peptide of the invention.

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Sugar Land, TX, United States of America

Timothy P Kogan