Optimization of a novel piperazinone series as potent selective peripheral covalent BTK inhibitors

Bin Ma; Claire M Metrick; Chungang Gu; Marc Hoemberger; Bekim Bajrami; Eris Bame; Jiansheng Huang; Michael Mingueneau; Paramasivam Murugan; Joseph C Santoro; Hao Tang; Ti Wang; Brian T Hopkins

doi:10.1016/j.bmcl.2022.128549

Optimization of a novel piperazinone series as potent selective peripheral covalent BTK inhibitors

Bioorg Med Chem Lett. 2022 Mar 15:60:128549. doi: 10.1016/j.bmcl.2022.128549. Epub 2022 Jan 15.

Authors

Bin Ma¹, Claire M Metrick², Chungang Gu³, Marc Hoemberger⁴, Bekim Bajrami⁵, Eris Bame⁶, Jiansheng Huang³, Michael Mingueneau⁷, Paramasivam Murugan⁴, Joseph C Santoro⁴, Hao Tang⁷, Ti Wang⁴, Brian T Hopkins⁸

Affiliations

¹ Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
² Biophysics, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
³ Drug Metabolism & Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
⁴ Bioassays & High-Throughput Screens, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
⁵ Chemical Biology & Proteomics, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
⁶ Translational Science, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
⁷ Multiple Sclerosis and Neurorepair Research, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
⁸ Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, MA 02142, USA. Electronic address: Brian.Hopkins@Biogen.com.

PMID: 35041943
DOI: 10.1016/j.bmcl.2022.128549

Abstract

BTK is a tyrosine kinase playing an important role in B cell and myeloid cell functions through B cell receptor (BCR) signaling and Fc receptor (FcR) signaling. Selective inhibition of BTK has the potential to provide therapeutical benefits to patients suffering from autoimmune diseases. Here we report the design, optimization, and characterization of novel potent and highly selective covalent BTK inhibitors. Starting from a piperazinone hit derived from a selective reversible inhibitor, we solved the whole blood cellular potency issue by introducing an electrophilic warhead to reach Cys481. This design led to a covalent irreversible BTK inhibitor series with excellent kinase selectivity as well as good whole blood CD69 cellular potency. Optimization of metabolic stability led to representative compounds like 42, which demonstrated strong cellular target occupancy and inhibition of B-cell proliferation measured by proximal and distal functional activity.

Keywords: B cell; BTK; Covalent inhibitor; Piperazinone; Selectivity; X-ray.

MeSH terms

Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
Agammaglobulinaemia Tyrosine Kinase / metabolism
B-Lymphocytes / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Humans
Molecular Structure
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Piperazines
Protein Kinase Inhibitors
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human