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Your search keyword '"Kowalski JA"' showing total 2 results
Start Over Author "Kowalski JA" Topic chemistry, pharmaceutical
2 results on '"Kowalski JA"'

1. 5-Aminomethylbenzimidazoles as potent ITK antagonists.

Author

Riether D, Zindell R, Kowalski JA, Cook BN, Bentzien J, Lombaert SD, Thomson D, Kugler SZ Jr, Skow D, Martin LS, Raymond EL, Khine HH, O'Shea K, Woska JR Jr, Jeanfavre D, Sellati R, Ralph KL, Ahlberg J, Labissiere G, Kashem MA, Pullen SS, and Takahashi H

Subjects
Animals, Benzimidazoles pharmacology, CD3 Complex biosynthesis, Drug Design, Enzyme Inhibitors pharmacology, Female, Hepatocytes metabolism, Humans, Inhibitory Concentration 50, Mice, Mice, Inbred BALB C, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Benzimidazoles chemical synthesis, Chemistry, Pharmaceutical methods, Enzyme Inhibitors chemical synthesis, Protein-Tyrosine Kinases antagonists & inhibitors
Abstract

Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described.

Published
2009
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2. Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors.

Author

Snow RJ, Abeywardane A, Campbell S, Lord J, Kashem MA, Khine HH, King J, Kowalski JA, Pullen SS, Roma T, Roth GP, Sarko CR, Wilson NS, Winters MP, Wolak JP, and Cywin CL

Subjects
Adenosine Triphosphate chemistry, Benzimidazoles chemical synthesis, Binding Sites, Drug Evaluation, Preclinical methods, Enzyme Inhibitors pharmacology, Humans, Hydrogen Bonding, Inhibitory Concentration 50, Models, Chemical, Protein Binding, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Benzimidazoles chemistry, Chemistry, Pharmaceutical methods, Protein Kinase Inhibitors chemical synthesis, Protein-Tyrosine Kinases antagonists & inhibitors
Abstract

Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.

Published
2007
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