E.i. Dupont De Nemours and Company

The Dupont Merck Pharmaceutical Company

Bristol-myers Squibb Compnay

Tufts University

New England Medical Center Hospitals. Inc.

Charles A Kettner

Ashokkumar Bhikkappa Shenvi

Bruce D Korant

John Matthew Fevig

William W Bachovchin

Timothy Patrick Forsyth

Andrew G Plaut

David J Carini

Matthew M Abelman

Joseph Cacciola

Gregory James Pacofsky

Eugene Cruz Amparo

Chia-Lin J Wang

Zixia Feng

Efraim Racker

Sharada Jagannathan

Padmaja Mantri

Sheng-Lian O Lee

&agr;-aminoboronic acids prepared by novel synthetic methods

This invention relates to Novel .alpha.-aminoacid and .alpha.-aminoboronic acid and corresponding peptide analogs of the following formula: ##STR1##

Amidino and guanidino substituted boronic acid inhibitors of

The present invention relates to the discovery of new C-terminal boronic acid dipeptide inhibitors of trypsin-like enzymes such as thrombin and pharmaceutical compositions thereof.

Dipeptide boronic acid inhibitors of trypsin-like enzymes

A method for the removal of ester protecting groups from .alpha.-amino boronic acid is disclosed for the preparation of compounds of formula (II) below

Removal of boronic acid protecting groups by transesterification

Intermediates for the preparation of Peptides comprising C-terminal boronic acid derivatives of lysine, ornithine, and arginine, homoarginine and corresponding isothiouronium analogs thereof, are reversible inhibitors of trypsin-like serine proteases such as thrombin, plasma kallikrein and plasmin.

Intermediates for preparing peptide boronic acid inhibitors of

Peptides comprising C-terminal boronic acid derivatives of lysine, ornithine, and arginine, homoarginine and corresponding isothiouronium analogs thereof, are reversible inhibitors of trypsin-like serine proteases such as thrombin, plasma kallikrein and plasmin.

Peptide boronic acid inhibitors of trypsin-like proteases

A method for preparing selected peptide substrates for detecting the activity of virus-specified proteases is provided. Specific tetrapeptide substrates are disclosed which are conjugates of protease-cleavable indicator groups and peptide sequences resembling picornavirus protease cleavage recognition sites.

Peptide substrates for detecting virus-specified protease activity

A compound having the structure ##STR1## where T is of the fomrula ##STR2## where each D.sup.1 and D.sup.2, independently, is a hydroxyl group of a group which is capable of being hydrolysed to a hydroxyl group in aqueous solution at physiological pH; a group of the formula ##STR3## where G is either H,F or an alkyl group containing 1 to about 20 carbon atoms and optional heteroatoms which can be N, S, or O; or a phosphonate group of the formula ##STR4## where J is O-alkyl, N-alkyl, or alkyl, each comprising about 1-20 carbon atoms and, optionally, heteroatoms which can be N, S, or O; T being able to form a complex with the catalytic site of an enzyme, X is a group having at least one amino acid, ##STR5## and each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is separately a group which does not interfere significantly (i.e., does not lower than Ki of the compound to less than 10.sup.-7 M) with site-specific recognition of the compound by the enzyme, and allows a complex to be formed with the enzyme.

Protease inhibitors

Certain peptide methyl ketone derivatives inhibit picornavirus replication by inhibition of virus-specified protease activity.

Tetrapeptide methyl ketone inhibitors of viral proteases

A general method for preparing specific inhibitors of virus-specified proteases is disclosed. The inhibitors comprise a halomethyl ketone or methyl ketone moiety covalently linked to a peptide sequence of three, four or five amino acids or amino acid residues, which peptide sequence corresponds to an amino acid sequence found adjacent to and upstream of a cleavage site recognized by a virus-specified protease.

Method for preparing specific inhibitors of virus-specified proteases

Selected tripeptide and tetrapeptide halomethyl ketones are employed in processes for treating viral infection in mammals. These compounds inhibit picornavirus protease activity.

Inhibition of viral protease activity by peptide halomethyl ketones

Peptide and amino acid halomethyl ketones are employed in processes for inhibiting cyclic nucleotide independent protein kinase activity and tumor cell growth.

Inhibition of cyclic nucleotide independent protein kinases

Peptides comprising C-terminal .alpha.-aminoboronic acid residues are potent, reversible inhibitors of proteolytic enzymes.

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Wilmington, DE, United States of America

Charles A Kettner