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2 results on '"Bremer MC"'

1. Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability.

Author

Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, Eigenbrot C, Gallion S, Johnson AR, Kropf JE, Lee SH, Liu L, Lubach JW, Macaluso J, Maciejewski P, Mitchell SA, Ortwine DF, Di Paolo J, Reif K, Scheerens H, Schmitt A, Wang X, Wong H, Xiong JM, Xu J, Yu C, Zhao Z, and Currie KS

Subjects
Agammaglobulinaemia Tyrosine Kinase, Animals, Dogs, Humans, Mice, Microsomes, Liver metabolism, Models, Molecular, Protein Kinase Inhibitors metabolism, Protein Kinase Inhibitors pharmacokinetics, Protein-Tyrosine Kinases metabolism, Pyridazines metabolism, Pyridazines pharmacokinetics, Pyrimidinones metabolism, Pyrimidinones pharmacokinetics, Rats, Thiophenes metabolism, Thiophenes pharmacokinetics, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Pyridazines chemistry, Pyridazines pharmacology, Pyrimidinones chemistry, Pyrimidinones pharmacology, Thiophenes chemistry, Thiophenes pharmacology
Abstract

BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2016
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2. Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834.

Author

Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, Gallion S, Hymowitz SG, Kropf JE, Lee SH, Liu L, Lubach JW, Macaluso J, Maciejewski P, Maurer B, Mitchell SA, Ortwine DF, Di Paolo J, Reif K, Scheerens H, Schmitt A, Sowell CG, Wang X, Wong H, Xiong JM, Xu J, Zhao Z, and Currie KS

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
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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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