Merck + Co., Inc.

Other

Bristol-myers Squibb Compnay

Boehringer Ingelheim Pharmaceuticals, Inc.

Bristol Meyers Squibb Company

Raymond A Firestone

Burton G Christensen

Paul E Finke

James B Doherty

Shrenik K Shah

Lovji D Cama

Dalton King

Kevan R Thompson

William K Hagmann

Gene Michael Dubowchik

William J Leanza

Pamela A Trail

Leila A Telan

Ronald W Ratcliffe

Stefan Peters

David B Johnston

Wolfgang J Rettig

Pilar Garin-Chesa

Juergen Mack

John Edward Park

Martin Lenter

Morris Zimmerman

Bonnie M Ashe

Peter L Barker

John L Fahey

Dietmar Leipert

Shrenik S Shah

Disclosed are enzyme-activated anti-tumor and anti-metastatic prodrug compounds. The specific enzymes are collagenase(IV) and elastase. Also disclosed are methods of making and using such compounds.

Enzyme-activated anti-tumor prodrug compounds

Conjugates containing a targeting ligand, such as an antibody, a therapeutically active drug and a branched peptide linker. The branched peptide linker contains two or more amino acid moieties that provide an enzyme cleavage site. The number of drugs capable of being bonded to the branched linkers varies by a factor of two for each generation of branching.

Branched peptide linkers

The invention relates to a prodrug that is capable of being converted into a drug by the catalytic action of human fibroblast activation protein (FAP&agr;), said prodrug having a cleavage site which is recognised by FAP&agr;, and said drug being cytotoxic or cytostatic under physiological conditions.

FAP-activated anti-tumour compounds

Branched hydrazone linkers for linking a targeting ligand such as an antibody to a therapeutically active drug. The point of branching is at a polyvalent atom and the number of drugs increases by a factor of two for each generation of branching. A preferred drug is doxorubicin.

Branched hydrazone linkers

The present invention relates to drug-ligand conjugates wherein the drug is linked to the ligand through a protein peptide linker and a connector, a process for the preparation of the conjugates, method of controlling the growth of undesirable cells, pharmaceutical compositions, and intermediates thereof.

Lysosomal enzyme-cleavable antitumor drug conjugates

A method is provided for treating hematologic tumors and solid tumors, including certain types of leukemias and metastatic tumors, having high LDL requirements employing a delipidating agent such as an MTP inhibitor to substantially reduce LDL blood levels. In addition, a method is provided for treating tumors of the above types having high LDL requirements, especially hematologic tumors such as certain leukemias, employing a delipidating compound to substantially remove native LDL, and then administering a cytotoxic agent carried in reconstituted LDL.

Method for treating tumors having high LDL requirements employing MTP

New substituted cephalosporin sulfones are found to be potent elastase inhibitors and thereby useful anti-inflammatory/antidegenerative agents.

Substituted cephalosporin sulfones as anti-inflammatory and

Organic sulfoxides having a latent allyl group bound to the sulfur are enzyme inhibitors of the suicide or K.sub.cat type.

Allylsulfoxide enzyme inhibitors

The present invention is concerned with the preparation of lysosomotropic detergent agents and pharmaceutical composition useful in the treatment of cancer. These compounds are amine derivatives having a pK of 3.5 of the general structure ##STR1## in which R.sub.1 is C.sub.8-30 alkyl, C.sub.8-30 -alkenyl, substituted C.sub.4-30 alkyl or substituted C.sub.4-30 -alkenyl; R.sub.2 is hydrogen or C.sub.1-4 alkyl and Y is an electron withdrawing group, to control the pK, selected from trifluoroethyl, and difluoroethyl.

Lysosometropic detergent therapeutic agents

New substituted azetidinones are found to be potent elastase inhibitors and thereby useful anti-inflammatory/antidegenerative agents.

Substituted azetidinones as anti-inflammatory and antidegenerative agents

Substituted cephalosporins are found to be potent elastase inhibitors and thereby useful antiinflammatory/antidegenerative agents.

Growing community of inventors

Fanwood, NJ, United States of America

Raymond A Firestone