2. Academic Validation
  3. Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834

Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834

  • Bioorg Med Chem Lett. 2015 Mar 15;25(6):1333-7. doi: 10.1016/j.bmcl.2015.01.032.
Wendy B Young 1,  James Barbosa 2,  Peter Blomgren 2,  Meire C Bremer 1,  James J Crawford 1,  Donna Dambach 1,  Steve Gallion 3,  Sarah G Hymowitz 1,  Jeffrey E Kropf 2,  Seung H Lee 2,  Lichuan Liu 1,  Joseph W Lubach 1,  Jen Macaluso 2,  Pat Maciejewski 2,  Brigitte Maurer 1,  Scott A Mitchell 2,  Daniel F Ortwine 1,  Julie Di Paolo 2,  Karin Reif 1,  Heleen Scheerens 1,  Aaron Schmitt 2,  C Gregory Sowell 1,  Xiaojing Wang 1,  Harvey Wong 1,  Jin-Ming Xiong 2,  Jianjun Xu 2,  Zhongdong Zhao 2,  Kevin S Currie 2
Affiliations

Affiliations

  • 1 Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
  • 2 Gilead Sciences, 36 East Industrial Rd., Branford, CT 06405, United States (formerly CGI Pharmaceuticals).
  • 3 St. Andrews Circle, Wallingford, CT 06492, United States.
PMID: 25701252 DOI: 10.1016/j.bmcl.2015.01.032
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.

Keywords

Amide hydrolysis; Bruton’s tyrosine kinase; Btk; GDC-0834; Kinase inhibitor; Rheumatoid arthritis; Single dose IND.

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