Discovery Of The Bruton'S Tyrosine Kinase Inhibitor Clinical Candidate Tak-020 (S)-5-(1-((1-Acryloylpyrrolidin-3-Yl)Oxy)Isoquinolin-3-Yl)-2,4-Dihydro-3 H-1,2,4-Triazol-3-One, By Fragment-Based Drug Design

This publication details the successful use of FBDD (fragment-based drug discovery) principles in the invention of a novel covalent Bruton's tyrosine kinase inhibitor, which ultimately became the Takeda Pharmaceuticals clinical candidate TAK-020. Described herein are the discovery of the fragment 5-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one, the subsequent optimization of this hit molecule to the candidate, and synthesis and performance in pharmacodynamic and efficacy models along with direct biophysical comparison of TAK-020 with other clinical-level assets and the marketed drug Ibrutinib.