Mohamed Iqbal

Discovery of a Potent, Selective, and Orally Active Proteasome Inhibitor for the Treatment of Cancer

The ubiquitin-proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[(2 S,3 R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.

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.

Identification of a Chymotrypsin‐Like Mast Cell Protease in Rat Brain Capable of Generating the N‐Terminus of the Alzheimer Amyloid β‐Protein

Abstract: Cleavage after Met596 of the β‐amyloid precursor protein to generate the N‐terminus of β‐protein indicates the activity of a protease having chymotrypsin‐like specificity. A chymotrypsin‐like protease is further implicated in Alzheimers disease by the increased synthesis of the protease inhibitor α1‐antichymotrypsin in pathologically affected brain regions and by the presence in the amyloid deposits of inactivated forms of α1‐antichymotrypsin (indicating irreversible binding to a target chymotrypsin‐like protease). In the present report, we have purified from rat brain a chymotrypsin‐like protease that (a) binds with high affinity to human α1‐antichymotrypsin, (b) proteolytically generates a β‐protein‐containing C‐terminal fragment from full‐length recombinant human β‐amyloid precursor protein, and (c) selectively cleaves methoxysuccinyl‐Glu‐Val‐Lys‐Met‐p‐nitroanilide (a substrate modeling the protease recognition domain for the β‐protein N‐terminal cleavage site). Amino acid sequences of tryptic fragments of the purified rat brain chymotrypsin‐like protease indicate an identity with rat mast cell protease I. Moreover, the ontogeny and compartmentalization of rat brain chymotrypsin‐like protease are consistent with those of connective tissue‐type mast cells in the meningeal and intracortical perivasculature. Because these areas in human brain form extensive β‐amyloid deposits in Alzheimers disease, Downs syndrome, and hereditary cerebral hemorrhage with amyloidosis of Dutch origin, the present findings suggest that a brain mast cell chymotrypsin‐like protease may participate in generating perivascular β‐protein, which ultimately aggregates into β‐amyloid deposits.

Subsite requirements for peptide aldehyde inhibitors of human calpain I

Abstract Dipeptide and tripeptide aldehydes have been evaluated as inhibitors of human calpain I. Dipeptide aldehydes are generally equipotent with tripeptide aldehydes. Calpain I possesses a rather stringent requirement for Leu at P2, but accepts a variety of capping groups and amino acids at P1 and P3. Several new peptide aldehydes that are more potent than previously reported calpain I inhibitors have been identified.

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.

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.

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.

Wake-promoting agents: Search for next generation modafinil: Part I

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.