Merck + Co., Inc.

Vertex Pharmaceuticals, Inc.

Other

Joshua S Boger

Daniel F Veber

Jeffrey O Saunders

Roger D Tung

Mark G Bock

David M Armistead

Harold V Meyers

Ben E Evans

Kathleen M Rupprecht

Emilio A Emini

Ellen B Bayne

John A Schmidt

David A Armistead

Philippe L Durette

Roger M Freidinger

Stephen F Brady

Richard A Mumford

Linda S Payne

Arsenio A Pessolano

Robert M DiPardo

Francis J Dumont

Matthew W Harding

John L Humes

Nolan H Sigal

Vivian M Larson

Mary Ellen Dahlgren

Joseph V Hughes

D T Davies

A immunoassay based on the detection of leukocyte-elastase produced fibrinogen cleavage peptides which allows the evaluation of the potency of compounds that inhibit formation of cleavage peptides in a variety of in vitro cell biological situations is provided. The assay may be employed to detect an endogenous leukocyte-elastase produced fibrinogen cleavage peptide signal in normal human plasma and at elevated levels in cystic fibrosis plasma and in rheumatoid arthritis synovial fluid samples. The assay procedure can be a single step assay which allows for the rapid and reproducible detection of specific cleavage peptides.

Assay for marker of human polymorphonuclear leukocyte elastase activity

The present invention relates to novel compounds which possess a broad range of useful biological activities. These compounds can maintain, increase, or restore sensitivity of cells to therapeutic or prophylactic agents. They can also suppress, modify, or significantly reduce an immune response, including an autoimmune response in a mammal. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well-suited for treatment of multi-drug resistant cells, for prevention of the development of multi-drug resistance, for use in multi-drug resistant cancer therapy, and for prevention or treatment of graft rejection and various autoimmune diseases.

Biologically active acylated amino acid derivatives

This invention relates to a novel class of immunosuppressive compounds having an affinity for the FK-506 binding protein (FKBP). Once bound to this protein, the immunosuppressive compounds inhibit the prolyl peptidyl cis-trans isomerase (rotamase) activity of the FKBP and inhibit T cell activation. As such, the compounds of this invention can be used as immunosuppressive drugs to prevent or significantly reduce graft rejection in bone marrow and organ transplantations and for use in the treatment of a wide variety of autoimmune diseases in humans and other mammals.

Immunosuppressive compounds

This invention relates to a novel class of immunosuppressive compounds having an affinity for the FK-506 binding protein (FKBP). Once bound to this protein, the immunosuppressive compounds inhibit the prolyl peptidyl cis-trans isomerase (rotamass) activity of the FKBP and inhibit T cell activation. As such, the compounds of this invention can be used as immunosuppressive drugs to prevent or significantly reduce graft rejection in bone marrow and organ transplantations and for use in the treatment of a wide variety of autoimmune diseases in humans and other mammals.

Several distinct peptide regions of the secreted form of purified human interleukin-1 species pI 6.8 have been found to exhibit characteristics associated with highly immunogenic protein moieties and are used to produce specific anti-peptide antibodies. The antibodies raised against the individual peptides are specific for the peptide used for their production and for IL-1, pI 6.8. The individual antibodies bind to both the precursor of IL-1, pI 6.8 and the mature or extracellular IL-1, pI 6.8.

Immunogenic peptides of human interleukin-1 and the corresponding

Positions 7- and/or 6-substituted 1,2,3,4,4a,9b-Hexahydro-8-hydroxydibenzofuran-3-ols and analogs of that general structure are described. These compounds are found to be potent inhibitors of 5-lipoxygenase, an enzyme crucial to the biosynthesis of leukotrienes and useful in the treatment of a variety of inflammatory conditions.

6- and/or

Certain trans-2,3-disubstituted-2,3-dihydro-5-hydroxybenzofurans are described. The synthesis involves an intramolecular Michael addition to yield the thermodynamic trans isomer. The compounds were found to be inhibitors of 5-lipoxygenase, an enzyme crucial to the biosynthesis of leukotrienes and useful for the treatment of various inflammatory diseases.

Trans 2,3-disubstituted-2,3-dihydro-5-hydroxy-benzofurans as inhibitors

Novel cyclosporin analogs containing a MeAla or MeAbu residue at the 6-position of the cyclic undecapeptide have been synthesized and found unexpectedly to exhibit antagonistic activity toward cyclosporin A binding to its cytosolic protein receptor, cyclophilin, without being immunosuppressive.

Novel 6-position cyclosporin analogs as non-immunosuppressive

Enzyme tripeptides of the formula: ##STR1## and analogs thereof which inhibit renin and are useful for treating various forms of renin-associated hypertension, hyperaldosteronism and congestive heart failure; compositions containing these renin-inhibitory peptides, optionally with other antihypertensive agents; and methods of treating hypertension, hyperaldosteronism or congestive heart failure or of establishing renin as a causative factor in these problems employing the novel tripeptides.

Tripeptide renin inhibitors

Renin inhibitory peptides of the formula ##STR1## and analogs thereof inhibit renin and are useful for treating various forms of renin-associated hypertension and hyperaldosteronism.

Renin inhibitors containing a C-terminal amide cycle

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Bryn Mawr, PA, United States of America

Joshua S Boger