Pyrrolo[2,3-d]pyrimidines active as Btk inhibitors

ABSTRACT

Introduction: Btk is a tyrosine kinase dysregulated in several B-cell malignancies and autoimmune diseases, and this has given rise to a search for Btk inhibitors. Nevertheless, only one Btk inhibitor, ibrutinib, has been approved to date, although other compounds are currently being evaluated in clinical trials or in preclinal stages.

Area covered: This review, after a brief introduction on Btk and its inhibitors already in clinical trials, focusses on pyrrolo[2,3-d]pyrimidine derivatives patented in the last five years as Btk inhibitors. Indeed, the pyrrolo[2,3-d]pyrimidine scaffold, being a deaza-isostere of adenine, the nitrogenous base of ATP, is an actively pursued target for Btk inhibitors. The patent literature since 2012 have been extensively investigated, pointing out the general features of the patented compounds and, when it is possible, their mechanism of action.

Expert opinion: The recently patented pyrrolo[2,3-d]pyrimidines, acting as reversible or irreversible inhibitors, showed a very interesting in vitro activity. For this reason, the development of compounds endowed with this scaffold could afford a significant impact in the search for drug candidates for the treatment of immune diseases or B-cell malignancies.

KEYWORDS:

• Autoimmune diseases
• B-cell neoplasias
• Btk
• inhibitors
• pyrrolo[2,3-d]pyrimidines
• tyrosine kinases

Article highlights

• Btk is a tyrosine kinase dysregulated in several B-cell malignancies and autoimmune diseases.

• Ibrutinib is the only Btk inhibitor which has been approved to date for the treatment of different lymphomas.

• Many small molecule Btk inhibitors endowed with different heterocyclic scaffolds are currently evaluated in clinical trials.

• The pyrrolo[2,3-d]pyrimidine structure has emerged as a promising core for the development of Btk inhibitors.

• Many irreversible or reversible Btk inhibitors endowed with a pyrrolo[2,3-d]pyrimidine nucleus has been patented in the last five years.

• A number of them possesses IC₅₀ values in the nanomolar/subnanomolar range on Btk.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.