Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents.

Abstract

BACKGROUND:

Chronic and oral administration of benzylamine improves glucose tolerance. Picolylamine is a selective functional antagonist of the human adenosine A2B receptor. Phosphonic diamide derivatives enhance the cellular permeability and in turn their biological activities.

METHODS:

A series of heteroaryl phosphonicdiamide derivatives were designed as therapeutics to control and manage type2 diabetes. Initially defined Lipinski parameters encouraged them as safer drugs. Molecular docking of these compounds against Protein tyrosine phosphatase (PTP), the potential therapeutic target of type 2 diabetes, revealed their potential binding ability explaining their anti-diabetic activity in terms of PTP inhibition. Human intestinal absorption, Caco-2 cell permeability, MDCK cell permeability, BBB penetration, skin permeability and plasma protein binding abilities of the title compounds were calculated by PreADMET server. A convenient method has been developed for the synthesis of title compounds through the formation of 1-ethoxy-N,N'-bis(4-fluorobenzyl/pyridin-3-ylmethyl)phosphinediamine by the reaction of 4-fluorobenzylamine/ 3-picolylamine with ethyldichlorophosphite, subsequently reacted with heteroaryl halides using lanthanum(III) chloride as a catalyst.

RESULTS:

All the compounds exhibited significant in vitro anti-oxidant activity and in vivo evaluation in streptozotocin induced diabetic rat models revealed that the normal glycemic levels were observed on 12(th) day by 9a and 20(th) day by 5b, 5c, 9e and 9f. The remaining compounds also exhibited normal glycemic levels by 25(th) day.

CONCLUSION:

The results from molecular modeling, in vitro and in vivo studies are suggesting them as safer and effective therapeutic agents against type2 diabetes. Graphical Abstract Development of PTPs inhibitors.

• Authors: Kuruva Chandra Sekhar, Rasheed Syed, Madhava Golla, Jyothi Kumar M V, Nanda Kumar Yellapu, Appa Rao Chippada, Naga Raju Chamarthi
• Journal: Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences (Daru) Vol. 22 Pg. 76 (Dec 27 2014) ISSN: 2008-2231 [Electronic] Switzerland
• PMID: 25542373 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Biomarkers
• Blood Glucose
• Enzyme Inhibitors
• Hypoglycemic Agents
• Phosphorus Compounds
• Protein Tyrosine Phosphatases

Topics

• Animals
• Antioxidants (pharmacology)
• Biomarkers (blood)
• Blood Glucose (drug effects, metabolism)
• Blood-Brain Barrier (metabolism)
• Caco-2 Cells
• Diabetes Mellitus, Experimental (blood, drug therapy)
• Diabetes Mellitus, Type 2 (blood, drug therapy)
• Disease Models, Animal
• Dogs
• Drug Design
• Enzyme Inhibitors (chemical synthesis, metabolism, pharmacology)
• Humans
• Hypoglycemic Agents (chemical synthesis, metabolism, pharmacology)
• Intestinal Absorption
• Madin Darby Canine Kidney Cells
• Male
• Molecular Docking Simulation
• Molecular Structure
• Permeability
• Phosphorus Compounds (chemical synthesis, metabolism, pharmacology)
• Protein Binding
• Protein Tyrosine Phosphatases (antagonists & inhibitors, metabolism)
• Rats, Wistar
• Skin Absorption
• Structure-Activity Relationship
• Time Factors