Torrey Pines Institute for Molecular Studies

Trega Biosciences, Inc.

Zymogenetics, Inc.

The Burnham Institute

Lion Bioscience Ag

Houghten Pharmaceuticals, Inc.

Torry Pines Institute for Molecular Studies

John M Ostresh

Richard Allen Houghten

Clemencia Pinilla

Adel Nefzi

Jean-Philippe Meyer

Charles R Petrie

Patricia A McKernan

Emma E Moore

Sylvie E Blondelle

John C Reed

Colette T Dooley

Jutta Eichler

Hassan M ElAbdellaoui

Kate Welsh

Barbara Dorner

Colette Dooley

Yongping Yu

Christa C Schoner

The invention provides isolated agents having novel chemical structures and possessing superior activity as derepressors of IAP inhibited caspase. The invention further provides a method of derepressing an IAP-inhibited caspase. The invention further provides assay methods employing labeled compounds of the invention, especially fluorescent labeled compounds.

Methods and compositions for derepression of IAP-inhibited caspase

The invention provides isolated agents having a core peptide selected from the group consisting of Core peptides 5 through 39 and 42 through 55, wherein the agent derepresses an IAP-inhibited caspase. Also provided is an isolated agent having a core structure selected from any of the structures shown in FIGS.B, andwherein said agent derepresses an IAP-inhibited caspase. The invention further provides a method of derepressing an IAP-inhibited caspase. The method consists of contacting an IAP-inhibited caspase with an effective amount of an agent to derepress an IAP-inhibited caspase, the agent having a core motif selected from the group consisting of a core peptide having a sequence set forth in any of Core peptides 4 through 39 and 42 through 55, and a core structure selected from the group consisting of TPI759, TPI882, TPI914 or TPI927. The methods of the invention also can be used for promoting apoptosis in a cell and for reducing the severity of a pathology characterized by reduced levels of apoptosis. Methods for identifying agents that derepress an IAP-inhibited caspase are also provided.

The solid-phase synthesis of individual 1,3-disubstituted and 1,3,5-trisubstituted-1,3,5-triazine-2,4,6-triones and libraries thereof from a resin is described. Reaction of resin-bound amino acids with isocyanates yields resin-bound ureas, which further react with chlorocarbonyl isocyanate to selectively afford the resin-bound 1,3-disubstituted-1,3,5-triazine-2,4,6-triones. Selective alkylation at the N-5 position of the resin-bound 1,3-disubstituted-1,3,5-triazine-2,4,6-triones produces a trisubstituted triazinetrione. The products are cleaved from their solid support and obtained in good yield and purity.

1,3,5- trisubstituted-1,3,5-triazine-2,4,6-trione compounds and libraries

The synthesis of individual di- and tri-substituted-1,4-diazacyclic compounds having 6- to 8-atoms in the cyclic ring, their corresponding 1,6-diketo-2,5-diazacyclic compounds and similar 1,4-diazacyclic ring compounds having one ring carbonyl gorup and 6-8 atoms in the ring is disclosed, as are libraries of such compounds. Methods of preparing and using the libraries of compounds as well as individual compounds of the libraries are also disclosed.

Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof

Individual substituted &lsqb;3,5,7&rsqb;-1H-imidazo&lsqb;1,5-a&rsqb;imidazol-2(3H)-one compounds and their pharmaceutically-acceptable salts are disclosed, as are libraries of such compounds. Methods of preparing and using the libraries of compounds as well as individual compounds of the libraries are also disclosed.

Synthesis of &lsqb;3,5,7&rsqb;-1H-imidazo &lsqb;1,5-a&rsqb;imidazol-2 (3H)- one compounds

Synthesis of &lsqb;3,5,7&rsqb;-H-imidazo&lsqb;1,5-a&rsqb; imidazol-2(3H)-one compounds

The synthesis of individual di- and tri-substituted-1,4-diazacyclic compounds having 6- to 8-atoms in the cyclic ring, their corresponding 1,6-diketo-2,5-diazacyclic compounds and similar 1,4-diazacyclic ring compounds having one ring carbonyl group and 6-8 atoms in the ring is disclosed, as are libraries of such compounds. Methods of preparing and using the libraries of compounds as well as individual compounds of the libraries are also disclosed.

Dialkyl urea compounds are described which act as calcitonin mimetics. These compounds are useful in the treatment of diseases which are associated with bone resorption. The calcitonin mimetics of the present invention are also useful in assays for the determination of calcitonin receptor activity.

Dialkyl ureas as calcitonin mimetics

The invention provides a rapid approach for combinatorial synthesis and screening of combinatorial libraries of bicyclic guanidine compounds. The present invention further provides the compounds made by the combinatorial synthesis and individually as well as methods of using the same.

Combinatorial libraries of bicyclic guanidine derivatives and compounds therein

The instant invention is directed to a single, selectively N-alkylated compound and libraries of such compounds as set forth in Formula I. Furthermore, the instant invention is directed to methods of effecting analgesia, a decrease in the postprandial rise in the blood glucose levels of a mammal after ingestion of a carbohydrate load by said mammal, and treating microbial infections, utilizing such a single compound of Formula I in conjunction with a pharmaceutically-acceptable carrier. Also, the instant invention is directed to methods for selective alkylation, positional scanning and iterative synthetic and screening technologies.

Selectively N-alkylated peptidomimetic combinatorial libraries and

The invention provides a rapid approach for combinatorial synthesis and screening of libraries of hydantoin and thiohydantoin compounds. The present invention further provides the compounds made by the combinatorial synthesis.

Combinatorial libraries of hydantoin and thiohydantoin derivatives,

The invention provides a rapid approach for combinatorial synthesis and screening of libraries of imidazol-pyrido-indole and imidazol-pyrido-benzothiophene compounds. The present invention further provides methods of preparing the libraries and the individual compounds made by the combinatorial synthesis.

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Encinitas, CA, United States of America

John M Ostresh