Potent and selective Bruton’s tyrosine kinase inhibitors: Discovery of GDC-0834
| Autor: | Aaron C. Schmitt, Donna Dambach, Jen Macaluso, Kevin S. Currie, Xiaojing Wang, James Barbosa, Sarah G. Hymowitz, Kropf Jeffrey E, Steve Gallion, Peter Blomgren, Lichuan Liu, Scott A. Mitchell, Julie Di Paolo, Jin-Ming Xiong, Joseph W. Lubach, Pat Maciejewski, C. Gregory Sowell, Heleen Scheerens, Seung H. Lee, Karin Reif, Zhongdong Zhao, Wendy B. Young, Jianjun Xu, Harvey Wong, Brigitte Maurer, Daniel F. Ortwine, James J. Crawford, Meire Bremer |
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| Rok vydání: | 2015 |
| Předmět: |
Drug
media_common.quotation_subject Clinical Biochemistry Pharmaceutical Science Pyrimidinones Thiophenes Molecular Dynamics Simulation Pharmacology Crystallography X-Ray Biochemistry Mice Structure-Activity Relationship Dogs Pharmacokinetics Healthy volunteers Drug Discovery Agammaglobulinaemia Tyrosine Kinase Animals Humans Moiety Bruton's tyrosine kinase Potency Peptide bond Protein Kinase Inhibitors Molecular Biology media_common Binding Sites biology Chemistry Organic Chemistry Protein-Tyrosine Kinases Bridged Bicyclo Compounds Heterocyclic In vitro Protein Structure Tertiary Rats Benzamides Microsomes Liver biology.protein Molecular Medicine Half-Life Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25(6):1333-1337 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2015.01.032 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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