Abstract |
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.
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Authors | T Santhosh Kumar, Tiehong Yang, Shilpi Mishra, Chunxia Cronin, Saibal Chakraborty, Jian-Bing Shen, Bruce T Liang, Kenneth A Jacobson |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 56
Issue 3
Pg. 902-14
(Feb 14 2013)
ISSN: 1520-4804 [Electronic] United States |
PMID | 23286881
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
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Chemical References |
- Cardiotonic Agents
- Esters
- Organophosphonates
- Phosphates
- Adenosine
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Topics |
- 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
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