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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...

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Autores principales: Sekhar, Kuruva Chandra, Syed, Rasheed, Golla, Madhava, MV, Jyothi Kumar, Yellapu, Nanda Kumar, Chippada, Appa Rao, Chamarthi, Naga Raju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305230/
https://www.ncbi.nlm.nih.gov/pubmed/25542373
http://dx.doi.org/10.1186/s40199-014-0076-3
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author Sekhar, Kuruva Chandra
Syed, Rasheed
Golla, Madhava
MV, Jyothi Kumar
Yellapu, Nanda Kumar
Chippada, Appa Rao
Chamarthi, Naga Raju
author_facet Sekhar, Kuruva Chandra
Syed, Rasheed
Golla, Madhava
MV, Jyothi Kumar
Yellapu, Nanda Kumar
Chippada, Appa Rao
Chamarthi, Naga Raju
author_sort Sekhar, Kuruva Chandra
collection PubMed
description 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. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40199-014-0076-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-43052302015-02-03 Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents Sekhar, Kuruva Chandra Syed, Rasheed Golla, Madhava MV, Jyothi Kumar Yellapu, Nanda Kumar Chippada, Appa Rao Chamarthi, Naga Raju Daru Research Article 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. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40199-014-0076-3) contains supplementary material, which is available to authorized users. BioMed Central 2014-12-27 /pmc/articles/PMC4305230/ /pubmed/25542373 http://dx.doi.org/10.1186/s40199-014-0076-3 Text en © Sekhar et al.; licensee BioMed Central. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Sekhar, Kuruva Chandra
Syed, Rasheed
Golla, Madhava
MV, Jyothi Kumar
Yellapu, Nanda Kumar
Chippada, Appa Rao
Chamarthi, Naga Raju
Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents
title Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents
title_full Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents
title_fullStr Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents
title_full_unstemmed Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents
title_short Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents
title_sort novel heteroaryl phosphonicdiamides ptps inhibitors as anti-hyperglycemic agents
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305230/
https://www.ncbi.nlm.nih.gov/pubmed/25542373
http://dx.doi.org/10.1186/s40199-014-0076-3
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