Novel N-pyrimidin-4-yl-3-amino-pyrrolo [3, 4-C] pyrazole derivatives as PKC kinase inhibitors: a patent evaluation of US2015099743 (A1)

ABSTRACT

Introduction: Protein kinase Cβ (PKCβ) is a member of the PKC family of serine/threonine kinases that has been implicated in the pathophysiology of diabetic complications. Developing small molecule drugs targeting this PKC isozyme is a rational approach for treating these disease states. PKCβ belongs to the conventional class of PKC and contains both regulatory and kinase domain. Numerous compounds of different chemical classes were designed targeting the kinase domain, but achieved very limited success in clinical trials.

Areas covered: This patent application reports the synthesis of about 100 new N-pyrimidin-4-yl-3-amino-pyrolo [3, 4-C] pyrazole derivatives and their competitive inhibition constant (Ki) for protein kinase C βII (PKCβII), one of the two splice variants of PKCβ. The compounds compete with ATP at the kinase domain of PKCβII, and inhibit with high potency having Ki values in the 0.1–181 nM range. The compounds are claimed to be selective towards PKCβI, PKCβII and PKCα over other protein kinases. Several routes of administration of these compounds are discussed for possible treatment of diabetes and related diseases.

Expert opinion: This is an important effort toward developing PKC-based drugs for diabetic complications. Further biological evaluations of these compounds are required before proceeding toward clinical trails.

KEYWORDS:

• Protein kinase C
• inhibitor
• diabetes
• isoform selectivity
• kinase domain
• crystal structure

Declaration of interest

The author has 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.