title: Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo.
abstract: The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Burch
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Kathy
authors.initials: K
authors.lastname: Barrett
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: DeVoss
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Goldsmith
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: M Hicham A
authors.initials: MH
authors.lastname: Ismaili
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lau
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Lin
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Zarrin
authors.affiliation: ‡Evotec (U.K.) Ltd., 114 Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: McEwan
authors.affiliation: ‡Evotec (U.K.) Ltd., 114 Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: John J
authors.initials: JJ
authors.lastname: Barker
authors.affiliation: §Evotec AG, Manfred Eigen Campus, Essener Bogen 7, D-22419 Hamburg, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Ellebrandt
authors.affiliation: §Evotec AG, Manfred Eigen Campus, Essener Bogen 7, D-22419 Hamburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kordt
authors.affiliation: §Evotec AG, Manfred Eigen Campus, Essener Bogen 7, D-22419 Hamburg, Germany.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Stein
authors.affiliation: §Evotec AG, Manfred Eigen Campus, Essener Bogen 7, D-22419 Hamburg, Germany.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Wang
authors.affiliation: ∥Pharmaron Beijing Ltd. Co., No. 6 TaiHe Road BDA, 100176 Beijing, P. R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: ∥Pharmaron Beijing Ltd. Co., No. 6 TaiHe Road BDA, 100176 Beijing, P. R. China.
authors.forename: Baihua
authors.initials: B
authors.lastname: Hu
authors.affiliation: ∥Pharmaron Beijing Ltd. Co., No. 6 TaiHe Road BDA, 100176 Beijing, P. R. China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Xu
authors.affiliation: ∥Pharmaron Beijing Ltd. Co., No. 6 TaiHe Road BDA, 100176 Beijing, P. R. China.
authors.forename: Po-Wai
authors.initials: PW
authors.lastname: Yuen
authors.affiliation: ∥Pharmaron Beijing Ltd. Co., No. 6 TaiHe Road BDA, 100176 Beijing, P. R. China.
authors.forename: Yamin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D018793:Interleukin-13 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013454:Sulfoxides / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: D003603:Cytotoxins; D007191:Indazoles; D018793:Interleukin-13; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D013450:Sulfones; D013454:Sulfoxides; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase