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
  • 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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