Chiron Corporation

Arris Pharmaceutical Corporation

Kerry L Spear

Steven Rosenberg

Eric J Martin

Barbara O Scott

Lutz Richter

Rajinder Paul Singh

Dane A Goff

Paul A Renhowe

John M Nuss

Ronald N Zuckermann

Richard A Goldsmith

Simon C Ng

Philip Glyn Jones

Noel Aaron Powell

Taleen G Hanania

Andrew Malcolm Bray

Reyna J Simon

Charles R Johnson

Steve Rosenberg

Robert Valerio

Heinz W Gschwend

Edward G Brown

Manoi C Desai

Charles K Marlowe

Aaron C Sigmund

Yazhong Pei

Linghong Xie

Urokinase receptor ligands

Effective urokinase-type plasminogen activator receptor antagonists have sequences selected from the group LNFGQYLWYT, LCFGCYLWYT, LNFGCYLWCT, LNFGQYLnAYT, LNFdSQYLWYT, LCFGCYLWY, LNFdSQYLnAYT, LNFGdCYLWCT, LCFdSCYLWYT, LCFdSCYLnAYT, LNFdSCYLWCT, or active analogs or active portions thereof.

Peptide analog inhibitors of urokinase receptor activity

The invention relates to libraries of cyclic organic compounds and method of producing and assaying such libraries. According to the invention, each cyclic organic compound is constructed from a starting material in the form of a solid surface derivatized with a starting resin. Compounds are reacted with the resin to add or to form a cyclic group. The reactions are preferable carried out using a split resin procedure so that different compounds can be reacted with a plurality of subamounts so as to increase the size of the library. For example, compounds are reacted with a solid support bound starting resin to obtain a compound which includes an aldehyde functional group wherein the aldehyde compound or compounds reacted with it have substituents which are varied such that a mixture of products is obtained. The invention further relates to methods of producing combinatorial libraries of cyclic organic compounds from substrate bound compounds by cleaving the compounds from the support after synthesizing is completed and to assaying libraries of such compounds.

Combinatorial libraries of substrate-bound cyclic organic compounds

A solid-phase method for the synthesis of N-substituted oligomers, such as poly (N-substituted glycines) (referred to herein as poly NSGs) is used to obtain oligomers, such as poly NSGs of potential therapeutic interest which poly NSGs can have a wide variety of side-chain substituents. Each N-substituted glycine monomer is assembled from two 'sub-monomers' directly on the solid support. Each cycle of monomer addition consists of two steps: (1) acylation of a secondary amine bound to the support with an acylating agent comprising a leaving group capable of nucleophilic displacement by --NH.sub.2, such as a haloacetic acid, and (2) introduction of the side-chain by nucleophilic displacement of the leaving group, such as halogen (as a solid support-bound .alpha.-haloacetamide) with a sufficient amount of a second sub-monomer comprising an --NH.sub.2 group, such as a primary amine, alkoxyamine, semicarbazide, acyl hydrazide, carbazate or the like. Repetition of the two step cycle of acylation and displacement gives the desired oligomers. The efficient synthesis of a wide variety of oligomeric NSGs using automated synthesis technology of the present method makes these oligomers attractive candidates for the generation and rapid screening of diverse peptidomimetic libraries. The oligomers of the invention, such as N-substituted glycines (i.e. poly NSGs) disclosed here provide a new class of peptide-like compounds not found in nature, but which are synthetically accessible and have been shown to possess significant biological activity and proteolytic stability. Combinatorial libraries of cyclic compounds are disclosed wherein the cyclic compounds are comprised of at least one ring structure derived from cyclization of a peptoid backbone. The diversity of product compounds is generated by the sequential addition of substituted submonomers. The combinatorial library includes 10 or more, preferably 100 or more, and more preferably 1,000 or more distinct and different compounds. The library includes each of the product compounds in retrievable and analyzable amounts and preferably includes at least one biologically active compound. Methods of synthesizing the combinatorial libraries and assay devices produced using the libraries are disclosed as is methodology for screening for and obtaining biologically active cyclic organic compounds.

Synthesis of N-substituted oligomers

Compounds of the invention inhibit urokinase plasminogen activator: ##STR1## where R.sub.1 is lower alkyl, lower alkenyl, lower alkynyl, aryl, aralkyl, aryl-alkenyl, aryl-alkynyl, aryl-cycloalkyl, unsubstituted or substituted with 1-3 halo, OH, NH.sub.2, lower alkyl, halo-lower alkyl, lower alkoxy, lower alkylamino, lower alkylthio, CN or NO.sub.2 ;

Compositions and methods for the prevention and treatment of immunomediated inflammatory disorders, especially for those disorders associated with the respiratory tract, are provided. More particularly, a tryptase inhibitor, typically a hydroxyaroyl or hydroxyheteroaroyl substituted dipeptide, is administered. Also provided by this invention are pharmaceutical compositions, typically aerosol or topical, as well as aerosol devices for administering these compositions intranasally.

Compositions and methods for the treatment of immunomediated

Growing community of inventors

Oakland, CA, United States of America

Kerry L Spear