title: Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834.
abstract: SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors.
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 (formerly CGI Pharmaceuticals).
authors.forename: James
authors.initials: J
authors.lastname: Barbosa
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States (formerly CGI Pharmaceuticals).
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: 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: Sarah G
authors.initials: SG
authors.lastname: Hymowitz
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States (formerly CGI Pharmaceuticals).
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Kropf
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States (formerly CGI Pharmaceuticals).
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 (formerly CGI Pharmaceuticals).
authors.forename: Jen
authors.initials: J
authors.lastname: Macaluso
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States (formerly CGI Pharmaceuticals).
authors.forename: Pat
authors.initials: P
authors.lastname: Maciejewski
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Maurer
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States (formerly CGI Pharmaceuticals).
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 (formerly CGI Pharmaceuticals).
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 (formerly CGI Pharmaceuticals).
authors.forename: Aaron
authors.initials: A
authors.lastname: Schmitt
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: C Gregory
authors.initials: CG
authors.lastname: Sowell
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 (formerly CGI Pharmaceuticals).
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Xiong
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States (formerly CGI Pharmaceuticals).
authors.forename: Jianjun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States (formerly CGI Pharmaceuticals).
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States (formerly CGI Pharmaceuticals).
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Currie
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004285:Dogs; D006207:Half-Life; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; C555057:CGI 1746; 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; D011744:Pyrimidinones; D013876:Thiophenes; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse
keywords: Amide hydrolysis; Bruton’s tyrosine kinase; Btk; GDC-0834; Kinase inhibitor; Rheumatoid arthritis; Single dose IND