Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents
Background Chronic and oral administration of benzylamine improves glucose tolerance. Picolylamine is a selective functional antagonist of the human adenosine A 2B receptor. Phosphonic diamide derivatives enhance the cellular permeability and in turn their biological activities. Methods A series of...
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Veröffentlicht in: | Daru 2014-12, Vol.22 (1), p.76-76, Article 76 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Background
Chronic and oral administration of benzylamine improves glucose tolerance. Picolylamine is a selective functional antagonist of the human adenosine A
2B
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. |
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ISSN: | 2008-2231 1560-8115 2008-2231 |
DOI: | 10.1186/s40199-014-0076-3 |