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

Wendy B Young; James Barbosa; Peter Blomgren; Meire C Bremer; James J Crawford; Donna Dambach; Charles Eigenbrot; Steve Gallion; Adam R Johnson; Jeffrey E Kropf; Seung H Lee; Lichuan Liu; Joseph W Lubach; Jen Macaluso; Pat Maciejewski; Scott A Mitchell; Daniel F Ortwine; Julie Di Paolo; Karin Reif; Heleen Scheerens; Aaron Schmitt; Xiaojing Wang; Harvey Wong; Jin-Ming Xiong; Jianjun Xu; Christine Yu; Zhongdong Zhao; Kevin S Currie

doi:10.1016/j.bmcl.2015.11.076

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

Bioorg Med Chem Lett. 2016 Jan 15;26(2):575-579. doi: 10.1016/j.bmcl.2015.11.076. Epub 2015 Nov 24.

Authors

Wendy B Young¹, James Barbosa², Peter Blomgren², Meire C Bremer¹, James J Crawford¹, Donna Dambach¹, Charles Eigenbrot¹, Steve Gallion³, Adam R Johnson¹, Jeffrey E Kropf², Seung H Lee², Lichuan Liu¹, Joseph W Lubach¹, Jen Macaluso², Pat Maciejewski², Scott A Mitchell², Daniel F Ortwine¹, Julie Di Paolo², Karin Reif¹, Heleen Scheerens¹, Aaron Schmitt², Xiaojing Wang¹, Harvey Wong¹, Jin-Ming Xiong², Jianjun Xu², Christine Yu¹, Zhongdong Zhao², Kevin S Currie²

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.
³ St. Andrews Circle, Wallingford, CT 06492, United States.

PMID: 26675441
DOI: 10.1016/j.bmcl.2015.11.076

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.

Keywords: Bruton’s tyrosine kinase (BTK); Kinase inhibitor; Pyridazinone; Rheumatoid arthritis.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo(b)thiophene-2-carboxamide
Protein Kinase Inhibitors
Pyridazines
Pyrimidinones
Thiophenes
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human
Btk protein, mouse