title: Novel N-pyrimidin-4-yl-3-amino-pyrrolo [3, 4-C] pyrazole derivatives as PKC kinase inhibitors: a patent evaluation of US2015099743 (A1).
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy , University of Houston , Houston , TX , USA.
authors.forename: Joydip
authors.initials: J
authors.lastname: Das
mesh_terms: D000818:Animals; D048909:Diabetes Complications / Q000188:drug therapy / Q000503:physiopathology; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000503:physiopathology; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D010330:Patents as Topic; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha
keywords: Protein kinase C; crystal structure; diabetes; inhibitor; isoform selectivity; kinase domain