Merck + Co., Inc.

The University of Texas System

The Administrators of the Tulane Educational Fund

Other

Dong-Mei Feng

Victor M Garsky

Raymond E Jones

Stephen F Brady

Karl A Folkers

Cyril Y Bowers

Allen I Oliff

Deborah DeFeo-Jones

Anders Ljungqvist

Daniel F Veber

Ruth F Nutt

Minoru Kubota

Scott D Kuduk

Joseph P Vacca

Mark G Bock

Neville J Anthony

Roger M Freidinger

William C Lumma, Jr

Michael R Wood

Thomas Joseph Tucker

Philip E Sanderson

Dai-Shi Su

Terry A Lyle

Robert J Gould

Thomas M Connolly

Kenneth J Stauffer

Jenny Miu-Chun Wai

Pui-Fun L Tang

Jenny M Wai

Jules A Shafer

S Dale Lewis

Anna Janceka

Pui-Fun Louisa Tang

N-Biphenyl(substituted methyl) aminocycloalkanecarboxamide derivatives are bradykinin B1 antagonists or inverse agonists useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin B1 pathway.

N-biphenylmethyl aminocycloalkanecarboxamide derivatives

N-Biphenyl(substituted methyl)aminocycloalkanecarboxamide derivatives are bradykinin B1 antagonists or inverse agonists useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin B1 pathway.

N-biphenyl(substituted methyl) aminocycloalkane-carboxamide derivatives

Chemical conjugates which comprise oligopeptides, having amino acid sequences that are selectively proteolytically cleaved by free prostate specific antigen (PSA), hydrophilic oligopeptide blocking groups and known cytotoxic agents are disclosed. Such conjugates are useful in the treatment of prostatic cancer and benign prostatic hypertrophy (BPH).

Conjugates useful in the treatment of prostate cancer

Chemical conjugates which comprise oligopeptides, having amino acid sequences that are selectively proteolytically cleaved by free prostate specific antigen (PSA) and known cytotoxic agents are disclosed. The conjugates of the invention are characterized by attachment of the cleavable oligopeptide to the oxygen atom at the 4-position on a vinca drug that has be desacetylated. Such conjugates are useful in the treatment of prostatic cancer and benign prostatic hypertrophy (BPH).

Oligopeptides which comprise amino acid sequences that are recognized and proteolytically cleaved by free prostate specific antigen (PSA) are described. Also described are assays which comprise such oligopeptides useful for determining free PSA protease activity in vitro and in vivo. Therapeutic agents which comprise conjugates of such oligopeptides and known cytotoxic agents are also described.

Peptides

Chemical conjugates which comprise oligopeptides, having amino acid sequences that are selectively proteolytically cleaved by free prostate specific antigen (PSA) and known cytotoxic agents are disclosed. Such conjugates are useful in the treatment of prostatic cancer and benign prostatic hypertrophy (BPH).

Antide is the decapeptide, N-Ac-D-2-Nal,D-pClPhe, D-3-Pal, Ser,NicLys, D-NicLys, Leu, ILys, Pro, D-Ala,NH.sub.2 which is an antagonist of luteinizing hormone releasing hormone (LHRH). This decapeptide, like others of the present invention, has high antiovulatory activity (AOA) and releases negligible histamine. Antide is scheduled for scale-up, safety testing and evaluation in the experimental primate and in clinical medicine. Numerous other peptides having structures related to Antide were prepared and tested. These peptides had variations primarily in positions 5, 6, 7, and 8. Of these, N-Ac-D-2-Nal, D-pClPhe,D-3-Pal,Ser,PicLys,cis-DPzACAla,Leu,ILys,Pro,D-Ala-NH.sub.2 was one of the most potent and had higher antiovulatory activity than Antide, i.e. 73%/0.25 ug and 100%/0.5 ug vs. 36%/0.5 ug and 100%/1.0 ug. Antide showed significant, (p&lt;0.001) duration of action, when injected at a dose of 10 ug, 44 hours before 50 ng of the agonist, �D-3-Qal.sup.6 !-LHRH. Antide showed oral AOA at 600 ug (73%) and at 1200 ug (100%) with negligible difference being found between water and corn oil oral formulations. In the antagonists prepared according to the present invention, arginine and its derivatives were not utilized. Lysine was converted into derivatives with acyl groups or with alkyl groups on the E-amino group. The amino acid ornithine was acylated or alkylated on the d-amino group. Both the L- and D- forms of lysine and the L-form of ornithine were used in synthesizing these acyl and alkyl derivatives. Structurally related intermediates were also synthesized. All together, many new peptides were synthesized by the basic and minimal concepts of ten variables for anti-ovulation activity and ten variables for histamine release, which may be independent or partially overlapping. On such a basis, the number of such peptides that can be designed becomes overwhelming, and every reasonable priority must be considered to reduce the number of peptides to be synthesized in the hope that a discovery will be realized.

Methods for using LHRH antagonists with low histamine release

Piperidine and hexahydropyridazine thrombin inhibitors

Thrombin receptor binding peptides

4-substituted cyclohexylamine derivatives which are thrombin catalytic site inhibitors and which are useful as anticoagulants. These compounds show selectivity for thrombin over other trypsin-like enzymes and have oral bioavailability. They have the formula ##STR1## for example ##STR2##

Thrombin inhibitors

Compounds of the invention have the following structure: ##STR1## for example ##STR2## These compounds inhibit thrombin and associated thrombosis.

Pyrrolidine thrombin inhibitors

LHRH antagonists similar to antide and congeners with higher water solubility have been synthesized by substitutions in positions 1, 5 or 6 with hydrophilic residues. These peptides have antiovulatory activity with minimal histamine releasing effect.

Antagonists of LHRH

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Blue Bell, PA, United States of America

Dong-Mei Feng