Optimization of the efflux ratio and permeability of covalent irreversible BTK inhibitors

https://doi.org/10.1016/j.bmcl.2018.09.018Get rights and content

Highlights

  • A novel series of covalent Btk inhibitors was discovered.

  • Hit molecules showed high ER.

  • Optimization of ER led to the discovery of the lead molecule.

Abstract

Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N-linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain. The hit molecules, however, displayed high P-gp mediated efflux ratio (ER) and poor A-B permeability in Caco-2 assay. By decreasing tPSA, installing steric hindrance and adjusting clogP, one top molecule 9 was discovered, which showed a 99% decrease in efflux ratio and a 90-fold increase in A-B permeability compared to hit molecule 1.

Section snippets

Acknowledgments

We appreciate the valuable suggestions from our colleagues Dr. Yanping Wang and Esther Cleary.

References (33)

  • A.B. Satterthwaite et al.

    The role of Bruton’s tyrosine kinase in B-cell development and function: a genetic perspective

    Immunol Rev

    (2000)
  • C. Brunner et al.

    Bruton’s tyrosine kinase is involved in innate and adaptive immunity

    Histol Histopathol

    (2005)
  • J.A. Di Paolo et al.

    Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis

    Nat Chem Biol

    (2011)
  • K.D. Puri et al.

    B-cell receptor signaling inhibitors for treatment of autoimmune inflammatory diseases and B-cell malignancies

    Int Rev Immunol

    (2013)
  • T. Robak et al.

    Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimmune disorders

    Expert Opin Invest Drugs

    (2012)
  • R.H. Advani et al.

    Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies

    J Clin Oncol

    (2013)
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