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

https://doi.org/10.1016/j.bmcl.2015.11.076Get rights and content

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.

Section snippets

Acknowledgments

We thank the BTK team members at Gilead (formerly CGI Pharmaceuticals Inc.), Genentech, ChemPartner, and AMRI for their contributions in generating the data for this manuscript. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515.

References and notes (14)

  • W.B. Young et al.

    Bioorg. Med. Chem. Lett.

    (2015)
  • M. Elagawany et al.

    Bioorg. Med. Chem. Lett.

    (2013)
  • A.B. Satterthwaite et al.

    Immunol. Rev.

    (2000)
  • R.C. Brunne et al.

    Histol. Histopathol.

    (2005)
  • J.A. Di Paolo et al.

    Nat. Chem. Biol.

    (2011)
  • K.D. Puri et al.

    Int. Rev. Immunol.

    (2013)
  • T. Robak et al.

    Expert Opin. Investig. Drugs

    (2012)
There are more references available in the full text version of this article.

Cited by (33)

  • Design and synthesis of novel substituted benzyl pyrrolopyrimidine derivatives as selective BTK inhibitors for treating mantle cell lymphoma

    2021, Bioorganic Chemistry
    Citation Excerpt :

    A large hydrophobic group extending to the hydrophobic pockets adjacent to the hinge region mediates hydrophobic interactions. The linker connects the warhead or terminal group extending to Cys481 or the solvent region in the enzyme (Fig. 1B) [14,19–22]. The 4-phenoxyphenyl group and pyridine-2-benzamide group are common hydrophobic groups in reported BTK inhibitors.

  • Pyridazine as a privileged structure: An updated review on anticancer activity of pyridazine containing bioactive molecules

    2021, European Journal of Medicinal Chemistry
    Citation Excerpt :

    In comparison to GDC-0834, analogue 26 displayed improved metabolic liability in human liver microsomes (−/+ NADPH), low clearance in human hepatocytes. In addition, molecule 26 revealed favorable DMPK properties and highly biochemical selectivity toward a panel of 228 kinases [81]. C-terminal Src kinase (CSK) is an adverse regulator of T cell activation, and the inhibitors targeting CSK may be important for immuno-oncology treatment.

  • Design, synthesis and biological evaluation of novel dithiocarbamate-substituted diphenylaminopyrimidine derivatives as BTK inhibitors

    2019, Bioorganic and Medicinal Chemistry
    Citation Excerpt :

    An array of structural related compounds have also progressed to preclinical or clinical trial studies, such as GS-4059,9 HM-71224,10,11 QL-47.12,13 Apart from these above covalent BTK inhibitors, some reversible agents14 including GDC-0834,15,16 GDC-0853,17 G-744,18 RN-48619 were exquisitely designed with better selectivity and safety for immunological indications20 and ibrutinib-resistant BTK C481S mutation21,22. Nevertheless, drug resistant and severe side effects are still inevitable during the treatment,23 which signifies the urgent need of developing novel BTK inhibitors with improved efficacy and reduced toxicity.

  • Discovery of pyrazolopyrimidine derivatives as potent BTK inhibitors with effective anticancer activity in MCL

    2019, Bioorganic Chemistry
    Citation Excerpt :

    Moreover, a number of covalent and noncovalent BTK inhibitors including GS-4059 (3) [27], CC-292 (4) [28], HM71224 (5) [29], PLS-123 (6) [30] and 7 [31] have been advanced to preclinical or clinical trials to treat autoimmune diseases (Fig. 1). All the above inhibitors share a common feature (Fig. 2A): an aromatic core structure to occupy the hinge region of BTK; a large hydrophobic group extending to the hydrophobic pockets beside the hinge region; on the other side, the linker connected the warheads in irreversible BTK inhibitors extending to Cys481 of BTK forming a covalent bind, or linkers attached to the terminal groups in reversible BTK inhibitors spreading to the solvent region (Fig. 2A) [26,32–34]. Among the reported BTK inhibitors, the piperidine ring, phenyl ring and pyrrole ring were the common linkers (Fig. 1).

  • The development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review

    2018, European Journal of Medicinal Chemistry
    Citation Excerpt :

    Structural information about the kinase is fundamental for optimal inhibitor design. If the structure of the kinase shows great plasticity, different ligands might induce different states of the kinase, as observed in multiple crystal structures in various conformations [105,106]. It is essential to rationally design BTK inhibitors with the desired profiles based on different structural states, which should be studied carefully.

View all citing articles on Scopus
View full text