2. Academic Validation
  3. Optimization of a novel piperazinone series as potent selective peripheral covalent BTK inhibitors

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.
Bin Ma 1,  Claire M Metrick 2,  Chungang Gu 3,  Marc Hoemberger 4,  Bekim Bajrami 5,  Eris Bame 6,  Jiansheng Huang 3,  Michael Mingueneau 7,  Paramasivam Murugan 4,  Joseph C Santoro 4,  Hao Tang 7,  Ti Wang 4,  Brian T Hopkins 8
Affiliations

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.

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