title: Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability.
abstract: BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties.
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Young
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: James
authors.initials: J
authors.lastname: Barbosa
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Blomgren
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Meire C
authors.initials: MC
authors.lastname: Bremer
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Donna
authors.initials: D
authors.lastname: Dambach
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: St. Andrews Circle, Wallingford, CT 06492, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Gallion
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Kropf
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Seung H
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Lichuan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lubach
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Jen
authors.initials: J
authors.lastname: Macaluso
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Pat
authors.initials: P
authors.lastname: Maciejewski
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Mitchell
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Di Paolo
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Karin
authors.initials: K
authors.lastname: Reif
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Heleen
authors.initials: H
authors.lastname: Scheerens
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Schmitt
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Xiong
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Yu
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Currie
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D004285:Dogs; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011744:Pyrimidinones / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C560621:N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo(b)thiophene-2-carboxamide; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011744:Pyrimidinones; D013876:Thiophenes; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse
keywords: Bruton’s tyrosine kinase (BTK); Kinase inhibitor; Pyridazinone; Rheumatoid arthritis