Back to Search
Start Over
Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Mar 15; Vol. 25 (6), pp. 1333-7. Date of Electronic Publication: 2015 Feb 07. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Agammaglobulinaemia Tyrosine Kinase
Animals
Benzamides chemistry
Benzamides metabolism
Binding Sites
Bridged Bicyclo Compounds, Heterocyclic chemistry
Bridged Bicyclo Compounds, Heterocyclic metabolism
Crystallography, X-Ray
Dogs
Half-Life
Humans
Mice
Microsomes, Liver metabolism
Molecular Dynamics Simulation
Protein Binding
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors pharmacokinetics
Protein Structure, Tertiary
Protein-Tyrosine Kinases metabolism
Pyrimidinones chemical synthesis
Pyrimidinones pharmacokinetics
Rats
Structure-Activity Relationship
Thiophenes chemical synthesis
Thiophenes pharmacokinetics
Protein Kinase Inhibitors chemistry
Protein-Tyrosine Kinases antagonists & inhibitors
Pyrimidinones chemistry
Thiophenes chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 25
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 25701252
- Full Text :
- https://doi.org/10.1016/j.bmcl.2015.01.032