Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors.

Abstract

Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.

• Authors: Jason D Burch, Kevin Lau, John J Barker, Fred Brookfield, Yong Chen, Yuan Chen, Charles Eigenbrot, Claire Ellebrandt, M Hicham A Ismaili, Adam Johnson, Daniel Kordt, Colin H MacKinnon, Paul A McEwan, Daniel F Ortwine, Daniel B Stein, Xiaolu Wang, Dirk Winkler, Po-Wai Yuen, Yamin Zhang, Ali A Zarrin, Zhonghua Pei
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 13 Pg. 5714-27 (Jul 10 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24918870 (Publication Type: Journal Article)

Chemical References

• Indazoles
• N-(1-(3-(dimethylamino)-1-phenylpropyl)-1H-pyrazol-4-yl)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide
• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases
• emt protein-tyrosine kinase

Topics

• Animals
• Crystallography, X-Ray
• Dogs
• Drug Design
• Humans
• Indazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Jurkat Cells
• Kinetics
• Mice
• Models, Molecular
• Protein Kinase Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Rats
• Solubility
• Structure-Activity Relationship