title: 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.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Burch
authors.forename: Kevin
authors.initials: K
authors.lastname: Lau
authors.forename: John J
authors.initials: JJ
authors.lastname: Barker
authors.forename: Fred
authors.initials: F
authors.lastname: Brookfield
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Claire
authors.initials: C
authors.lastname: Ellebrandt
authors.forename: M Hicham A
authors.initials: MH
authors.lastname: Ismaili
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.forename: Daniel
authors.initials: D
authors.lastname: Kordt
authors.forename: Colin H
authors.initials: CH
authors.lastname: MacKinnon
authors.forename: Paul A
authors.initials: PA
authors.lastname: McEwan
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Stein
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Wang
authors.forename: Dirk
authors.initials: D
authors.lastname: Winkler
authors.forename: Po-Wai
authors.initials: PW
authors.lastname: Yuen
authors.forename: Yamin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ali A
authors.initials: AA
authors.lastname: Zarrin
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019169:Jurkat Cells; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; C000591358:N-(1-(3-(dimethylamino)-1-phenylpropyl)-1H-pyrazol-4-yl)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase