Document Detail


5'-Phosphate and 5'-phosphonate ester derivatives of (N)-methanocarba adenosine with in vivo cardioprotective activity.
MedLine Citation:
PMID:  23286881     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Activation of a cardiac myocyte P2X4 receptor protects against heart failure. 5'-Phosphonate and 5'-phosphate analogues of AMP containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system could protect from heart failure by potentially activating this cardioprotective channel. Phosphoesters and phosphonodiesters were synthesized and administered in vivo via a miniosmotic pump in a mouse ischemic heart failure model and most significantly increased intact heart contractile function (echocardiography) compared to vehicle infusion. Several new thio and deuterated phosphate derivatives were protective in a calsequestrin (CSQ) overexpressing heart failure model. Diethyl (7, MRS4084) and diisopropyl (8, MRS4074) phosphotriesters were highly protective in the ischemic model. Substitution of 2-Cl with iodo reduced protection in the CSQ model. Diisopropyl ester 16 (MRS2978) of (1'S,2'R,3'S,4'R,5'S)-4'-(6-amino-2-chloropurin-9-yl)-2',3'-(dihydroxy)-1'-(phosphonoethylene)bicyclo[3.1.0]hexane was highly efficacious (CSQ), while lower homologue 1'-phosphonomethylene derivative 14 was inactive. Thus, we identified uncharged carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure, suggesting this as a viable and structurally broad approach.
Authors:
T Santhosh Kumar; Tiehong Yang; Shilpi Mishra; Chunxia Cronin; Saibal Chakraborty; Jian-Bing Shen; Bruce T Liang; Kenneth A Jacobson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2013-01-22
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-15     Completed Date:  2013-04-19     Revised Date:  2014-02-17    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  902-14     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosine / analogs & derivatives*,  chemistry,  pharmacology
Animals
Cardiotonic Agents / pharmacology*
Chromatography, High Pressure Liquid
Disease Models, Animal
Esters
Magnetic Resonance Spectroscopy
Mice
Myocardial Ischemia / prevention & control
Organophosphonates / chemistry*
Phosphates / chemistry*
Spectrometry, Mass, Electrospray Ionization
Grant Support
ID/Acronym/Agency:
R01 HL48225/HL/NHLBI NIH HHS; Z99 DK999999/DK/NIDDK NIH HHS; ZIA DK031127-06/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/Esters; 0/Organophosphonates; 0/Phosphates; K72T3FS567/Adenosine
Comments/Corrections

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