ABSTRACT
Gliflozins constitute an important class of compounds useful as sodium glucose co-transporter (SGLT2) inhibitors to treat type-II diabetes. They act by blocking sodium-glucose transport protein 2 which is responsible for re-absorption of glucose in the proximal convoluted tubule (PCT) of kidney and thus its inhibition reduces blood glucose level. There are a number of gliflozins which have been approved by drug regulatory bodies like FDA, EMA and PMDA whereas some others are in pipeline in their late developmental phases. The present review article offers a detailed account of synthetic strategies employed for the synthesis, alternate synthetic routes along with Structure Activity Relationship (SAR) studies of well-established as well as newly developed SGLT2 inhibitors.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucosides/pharmacology , Hypoglycemic Agents/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2/metabolism , Animals , Diabetes Mellitus, Type 2/metabolism , Dose-Response Relationship, Drug , Glucosides/chemical synthesis , Glucosides/chemistry , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Molecular Structure , Sodium-Glucose Transporter 2 Inhibitors/chemical synthesis , Sodium-Glucose Transporter 2 Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Alzheimer, the fourth leading cause of death embodies a key responsible event including formation of ß-amyloid protein clustering to amyloid plaque on blood vessels. The origin of above events is Amyloid precursor protein (APP) which is an integral membrane protein known for its function in synapses formation. Modern research had proposed that the over expression of DYRK1A (Dual specificity tyrosine phosphorylation regulated kinase1A, a family of protein kinases, positioned within the Down's syndrome critical region (DSCR) on human chromosome 21causes phosphorylation of APP protein resulting in its cleavage to Aß 40, 42 and tau proteins (regulated by beta and gamma secretase) which plays critical role in early onset of Alzheimer's disease (AD) detected in Down's syndrome (DS), leading to permanent functional and structural deformities which results ultimately into neuro-degeneration and neuronal death. Therefore, DYRK1A emerges as a potential target for prevention of neuro-degeneration and hence Alzheimer. Presently, the treatment methods for Down's syndrome, as well as Alzheimer's disease are extremely biased and represent a major deficiency for therapeutic necessities. We hereby, focus our review on the current status of the research and contributions in the development of DYRK1A inhibitors.
Subject(s)
Alzheimer Disease/drug therapy , Down Syndrome/drug therapy , Drug Discovery/methods , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Animals , Computer-Aided Design , Down Syndrome/metabolism , Down Syndrome/physiopathology , Humans , Molecular Targeted Therapy/methods , Neurogenesis/drug effects , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Dyrk KinasesABSTRACT
Diabetes has turned out to be an epidemic in the recent years all over the world, and today it has become a burden on the healthcare system. Over the years, with technological advancements, different classes of antidiabetic medications have emerged, like sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones, but these are often loaded with serious aftermaths like hypoglycemia, weight gain, cardiovascular and renal issues. Dipeptidyl peptidase-4 (DPP-4) inhibition is an exciting and new approach in the treatment of type-2 diabetes. DPP-4 inhibitors or "gliptins" are weight neutral, pose lesser risk of hypoglycemia, and provide a long-term post-meal glycemic control. In this review, an attempt has been made to investigate novel potential compounds that can be added to the existing list of anti-diabetic drugs.
