Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hin...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-06, Vol.55 (12), p.5901-5921 |
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| creator | Kulagowski, Janusz J Blair, Wade Bull, Richard J Chang, Christine Deshmukh, Gauri Dyke, Hazel J Eigenbrot, Charles Ghilardi, Nico Gibbons, Paul Harrison, Trevor K Hewitt, Peter R Liimatta, Marya Hurley, Christopher A Johnson, Adam Johnson, Tony Kenny, Jane R Bir Kohli, Pawan Maxey, Robert J Mendonca, Rohan Mortara, Kyle Murray, Jeremy Narukulla, Raman Shia, Steven Steffek, Micah Ubhayakar, Savita Ultsch, Mark van Abbema, Anne Ward, Stuart I Waszkowycz, Bohdan Zak, Mark |
| description | A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity. |
| doi_str_mv | 10.1021/jm300438j |
| format | Article |
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Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. 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Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.</description><subject>Animals</subject><subject>Cell Line</subject><subject>Imidazoles - chemistry</subject><subject>Janus Kinase 1 - antagonists & inhibitors</subject><subject>Janus Kinase 1 - chemistry</subject><subject>Janus Kinase 2 - antagonists & inhibitors</subject><subject>Janus Kinase 2 - chemistry</subject><subject>Models, Molecular</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Structure, Tertiary</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacokinetics</subject><subject>Pyridines - pharmacology</subject><subject>Rats</subject><subject>Substrate Specificity</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0L1OwzAUBWALgWgpDLwA8oIEQ8B27NQZUcVPoSodYI4c-0Y4SuJiJ0jl6TFq6cR0lu8e6R6Ezim5oYTR27pNCeGprA_QmApGEi4JP0RjQhhLWMbSEToJoSaEpJSlx2jEmMgpJ2yMlnMDXW8rq1VvXYddheetNerbJauN965x6423xnYQsAp46b6gwaozeOX6eIif714onncftrS98-EUHVWqCXC2ywl6f7h_mz0li9fH-exukaiUij4BQaQRpSwzIIKXUnGjtAKuKqoJNbkWtJSZyUDlNGd5ro0uOUynOZhMGKnTCbra9q69-xwg9EVrg4amUR24IRRxFiY5ixHp9ZZq70LwUBVrb1vlNxH9Olrs54v2Ylc7lC2YvfzbK4LLLVA6FLUbfBe__KfoB_01dsc</recordid><startdate>20120628</startdate><enddate>20120628</enddate><creator>Kulagowski, Janusz J</creator><creator>Blair, Wade</creator><creator>Bull, Richard J</creator><creator>Chang, Christine</creator><creator>Deshmukh, Gauri</creator><creator>Dyke, Hazel J</creator><creator>Eigenbrot, Charles</creator><creator>Ghilardi, Nico</creator><creator>Gibbons, Paul</creator><creator>Harrison, Trevor K</creator><creator>Hewitt, Peter R</creator><creator>Liimatta, Marya</creator><creator>Hurley, Christopher A</creator><creator>Johnson, Adam</creator><creator>Johnson, Tony</creator><creator>Kenny, Jane R</creator><creator>Bir Kohli, Pawan</creator><creator>Maxey, Robert J</creator><creator>Mendonca, Rohan</creator><creator>Mortara, Kyle</creator><creator>Murray, Jeremy</creator><creator>Narukulla, Raman</creator><creator>Shia, Steven</creator><creator>Steffek, Micah</creator><creator>Ubhayakar, Savita</creator><creator>Ultsch, Mark</creator><creator>van Abbema, Anne</creator><creator>Ward, Stuart I</creator><creator>Waszkowycz, Bohdan</creator><creator>Zak, Mark</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20120628</creationdate><title>Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors</title><author>Kulagowski, Janusz J ; 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| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2012-06, Vol.55 (12), p.5901-5921 |
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| subjects | Animals Cell Line Imidazoles - chemistry Janus Kinase 1 - antagonists & inhibitors Janus Kinase 1 - chemistry Janus Kinase 2 - antagonists & inhibitors Janus Kinase 2 - chemistry Models, Molecular Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Protein Structure, Tertiary Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacokinetics Pyridines - pharmacology Rats Substrate Specificity |
| title | Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors |
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