Wisconsin Alumni Research Foundation

The Boots Company Plc

Merck + Co., Inc.

Pharmacia & Upjohn Company

Elan Pharmaceuticals, Inc.

Daniel H Rich

Sweet K Gurwara

David J Buttle

Michael E Solomon

Alan J Barrett

Yvonne M Angell

Varghese John

Daniel F Veber

David Louis Brown

Barbara Jagodzinska

Shon R Pulley

Miroslav Malkovsky

Joseph B Moon

John Jacobs

Prakash Raman

Matthew G Bursavich

The invention relates to substituted piperidine, piperazine, morpholine and thiomorpholine compounds useful in the treatment of Alzheimer's disease and more specifically to compounds that are capable of inhibiting beta-secretase, an enzyme that cleaves amyloid precursor protein to produce amyloid beta peptide (A-beta), a major component of the amyloid plaques found in the brains of Alzheimer's sufferers. One embodiment of the invention relates to compounds having the structure: where Z is CR or N, and R, Rand Rare as described in the specification.

3,4-disubstituted, 3,5-disubstituted and 3,4,5-substituted piperidines

Disclosed is are methods of generating chemical structures of putative non-peptide inhibitors of biologically-active receptors. The method includes constructing a model of a receptor-ligand complex using empirical three-dimensional data of the receptor-ligand complex. The conformation of the binding site between the receptor and the ligand is then altered to yield novel conformations not exhibited in either the native receptor or the bound receptor. These conformations are then used to generate models of non-peptide chemical structures that are complementary in structure to the altered conformations of the binding site. In this fashion, chemical structures of putative non-peptide inhibitors of the altered conformation are revealed.

Method to design therapeutically important compounds

Disclosed are conjugates of A&bgr;-binding peptides and CsA analogs and conjugates of A&bgr;-binding peptides and FK506 Binding Peptide inhibitors. These conjugates chemically induce dimerization of either cyclophilin or FK506 Binding Peptide with A&bgr; peptide, a major component of amyloid plaques found in neurological disorders such as Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The conjugates are useful in the treatment of neurological diseases involving the formation of amyloid plaques because they inhibit and/or prevent the aggregation and deposition of A&bgr; peptide into plaques.

Cyclosporin a conjugates and uses therefor

Disclosed are cyclosporin analogs having amino acid residue substitutions at positions 1, 3, or 7 of the cyclosporin peptide backbone. Also disclosed are conjugates of these cyclosporin analogs in which an HIV protease inhibitor moiety is conjugated to the position-7 amino acid residue of the cyclosporin. These compounds simultaneously bind to and inhibit cyclophilin and HIV protease. The compounds have good bioavailability and potent HIV inhibitory activity. They are useful in the treatment and prevention of HIV-mediated disorders, including AIDS.

Non-Imuunosuppressive cyclosporins and their use in the prevention and treatment of HIV infection

The present invention relates generally to cyclosporin analogs, and more paritcularly to methods for the solid-phase synthesis and on-resin cyclization of cyclosporin analogs. Methods are described for the on-resin cyclization of sterically hindered compounds synthesized through solid phase synthesis techniques. The methods utilize solvent, temperature, and washing conditions that allow the efficient on-resin cyclization of compounds like analogs of cyclosporin A.

Solid phase synthesis of immunosuppressive agents

Compositions and methods are described for the synthesis of novel analogs of cyclosporin A, and the use of those analogs as immunostimulatory agents.

Immunostimulatory agents

A pharmaceutical composition comprising purified chymopapain and a reducing agent is presented. The purified chymopapain in this composition has a specific activity against 1 mM of N-.alpha.-benzoyl-DL-arginine p-nitroanilide at 40.degree. C. and pH 6.8 of between 3,000 and 4,500 units per mg, and contains less than 0.2% each of papaya proteinase III (PPIII), papain, and papaya proteinase IV (PPIV).

Pharmaceutical composition of purified chymopapain

Chymopapain and method of purifying it on an inhibitory dipeptide

Renin inhibitory peptides of the formula:

Renin inhibitory peptides

The invention is addressed to the preparation of 3-nitro-4-bromomethyl benzoic acid, as a new compound from which 3-nitro-4-bromomethyl benzoyl amide polystyrene resin can be prepared for solid synthesis of protected peptide acids and amides and separation thereof without cleavage of acid labile protecting groups or decomposition of aromatic acid groups and from which purified polypeptides can be formed.

Growing community of inventors

Madison, WI, United States of America

Daniel H Rich