Kinase array design, back to front: Biaryl amides

Most kinase-directed array strategies aim to add functionality to a fragment that binds in the purine subpocket of the ATP-site. Here, an alternative pharmacophore-guided array approach is described which set out to discover novel purine subpocket-binding groups. Results are shown for p38α and cFMS...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 18; no. 19; pp. 5285 - 5289
Main Authors:	Baldwin, Ian, Bamborough, Paul, Haslam, Claudine G., Hunjan, Suchete S., Longstaff, Tim, Mooney, Christopher J., Patel, Shila, Quinn, Jo, Somers, Don O.
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 01-10-2008 Elsevier
Subjects:	Adenosine Triphosphate - chemistry Amides - chemical synthesis Amides - chemistry Amides - pharmacokinetics Animals Biological and medical sciences cFMS Combinatorial Chemistry Techniques Crystallography, X-Ray Heterocyclic Compounds, 1-Ring - chemical synthesis Heterocyclic Compounds, 1-Ring - chemistry Heterocyclic Compounds, 1-Ring - pharmacokinetics Inhibitors Inhibitory Concentration 50 Kinase array design Medical sciences Miscellaneous Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors Models, Molecular Molecular Structure p38 MAP kinase p38a Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Rats Structure-Activity Relationship Structure-based drug design p38 MAP kinase Inhibitors Structure-based drug design Kinase array design cFMS p38a Benzotriazine derivatives Isoquinoline derivatives Molecular structure Enzyme Transferases Mitogen-activated protein kinase Amides X ray diffraction Signal transduction Structure activity relation Biphenyl derivatives Binding mode Inhibitor Chemical synthesis Benzisoxazole derivatives Crystalline structure
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Summary:	Most kinase-directed array strategies aim to add functionality to a fragment that binds in the purine subpocket of the ATP-site. Here, an alternative pharmacophore-guided array approach is described which set out to discover novel purine subpocket-binding groups. Results are shown for p38α and cFMS kinase, for which multiple different series with nanomolar potency were discovered. New kinase inhibitors can be found by synthesis of targeted arrays of compounds designed using system-based knowledge as well as through screening focused or diverse compounds. Most array strategies aim to add functionality to a fragment that binds in the purine subpocket of the ATP-site. Here, an alternative pharmacophore-guided array approach is described which set out to discover novel purine subpocket-binding groups. Results are shown for p38α and cFMS kinase, for which multiple distinct series with nanomolar potency were discovered. Some of the compounds showed potency in cell-based assays and good pharmacokinetic properties.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2008.08.051