John P. Mallamo

Knowledge Based Prediction of Ligand Binding Modes and Rational Inhibitor Design for Kinase Drug Discovery

toward kinase inhibitor discovery, with the result that several kinase inhibitors have been approved as drugs since 2001. The commercial success of imatinib (N-(4-methyl-3-(4-(pyridin-3yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-l)methyl)benzamide) has provided a clear incentive for the continued pursuit of kinase inhibitor design.

Potent α-ketocarbonyl and boronic ester derived inhibitors of proteasome

Abstract Potent and selective α-ketocarbonyl ( 8a–b ) and boronic ester ( 11 ) derived inhibitors of the chymotrypsin-like activity of proteasome , first member of a newly identified class of threonine proteases, are described.

XANTHENE DERIVED POTENT NONPEPTIDIC INHIBITORS OF RECOMBINANT HUMAN CALPAIN I

Abstract Novel and potent, xanthene derived reversible aldehyde (7c) and α-ketocarboxamide (10a), and irreversible fluoromethyl ketone (10b) inhibitors of recombinant human calpain I are described.

TrkA kinase inhibitors from a library of modified and isosteric Staurosporine aglycone

An immobilized Staurosporine aglycone isostere where one of the indole nitrogen atoms was replaced by carbon has been sequentially functionalized to generate compounds inhibiting TrkA kinase. In the first phase, initial screening of a library of C13-hydroxymethyl-7-oxo-indenopyrrolocarbazoles resulted in several potent compounds, one of which was further optimized to generate the corresponding carbamates on solid phase. Some of the major carbamate diastereomers were found to be several-fold more potent than their alcohol parents. Synthesis, SAR analysis, kinase selectivity, and anti-tumor properties of a TrkA inhibitor (12a) are discussed.

A simple synthetic protocol for the protection of amides, lactams, ureas, and carbamates

Abstract A new procedure for protecting the amide, lactam, urea, and carbamate NH group with a triphenylmethyl (Tr) group is described. The utility of this method is illustrated with molecules that contain other functional groups. A mild deprotection using trifluoroacetic acid makes this a useful method for attaching amide groups on resin for combinatorial synthesis.

Potent fluoromethyl ketone inhibitors of recombinant human calpain I

Abstract We report on a series of potent and selective dipeptide fluoromethyl ketone inhibitors of recombinant human calpain I. Compound 4f, having a tetrahydroisoquinoline containing urea motif as N-terminus capping group, is the most potent member ( k obs I = 276,000 M−1 s−1) of this class. This compound was shown to prefer calpain I by >36-fold and approximately 4-fold over the related cysteine proteases, cathepsin B and cathepsin L, respectively.

Calpain inhibitors based on the quiescent affinity label concept: high rates of calpain inactivation with leaving groups derived from N-hydroxy peptide coupling reagents.

A series of irreversible inhibitors of recombinant calpain has been synthesized and their rates of inactivation have been evaluated against calpain and cathepsin B, respectively. The design of the inhibitors was based on the quiescent affinity label concept. By choosing the appropriate affinity group and by employing leaving groups derived from N-hydroxy coupling reagents, good inhibitors of calpain with high rates of inactivation have been identified. However, poor aqueous stability limits their therapeutic utility.

Prodrug esters of the indolocarbazole CEP-751 (KT-6587)

Prodrug esters of the indolocarbazole CEP-751 (KT-6587) were prepared with the goal of identifying water soluble, stable but cleavable forms for intravenous dosing. A dipeptide proform Lys-beta-Ala (16, CEP-2563/KT-8391) was identified for advancement to clinical trials.

A convenient synthesis of 3-substituted pipecolic acid methyl esters

Abstract A practical synthesis of the title compounds ( 3a-c, e ) from commercially available 3-hydroxy-2-pyridine carboxylic acid ( 4 ) is reported. The key step in the synthetic sequence involves a Pd-catalyzed cross coupling reaction of the triflate 6 with the appropriate alkyl or aryl derivatives to generate the substituted picolinic acid esters 7a-b, 8 and 11 . Catalytic reduction of these picolinic acid esters provided the title compounds in good yields.

Exploration of the importance of the P2-P3-NHCO-moiety in a potent di- or tripeptide inhibitor of calpain I: insights into the development of nonpeptidic inhibitors of calpain I.

Calpain I, an intracellular cysteine protease, has been implicated in the neurodegeneration following an episode of cerebral ischemia. In this paper, we report on a series of peptidomimetic ketomethylene and carbamethylene inhibitors of recombinant human calpain I (rh calpain I). Our study reveals that the -NHCO-moiety (possible hydrogen-bonding site) at the P2-P3 region of a potent tripeptide or a dipeptide inhibitor of calpain I is not a strict requirement for enzyme recognition. Compounds 7d ((R)-2-isobutyl-4-oxo-4-(9-xanthenyl)butanoic acid ((S)-1-formyl-3-methyl)butyl amide), 31 ((R)-2-isobutyl-4-(2-sulfonylnaphthyl)butyric acid ((S)1-formyl-3-methyl)butyl amide) and 34 ((R)-2-isobutyl-4-(2-sulfoxylnaphthyl)butyric acid ((S)-1-formyl-3-methyl)butyl amide) which exhibited good activity in the enzyme assay, also inhibited calpain I in a human cell line.