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5'-Phosphate and 5'-phosphonate ester derivatives of (N)-methanocarba adenosine with in vivo cardioprotective activity.

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.
AuthorsT Santhosh Kumar, Tiehong Yang, Shilpi Mishra, Chunxia Cronin, Saibal Chakraborty, Jian-Bing Shen, Bruce T Liang, Kenneth A Jacobson
JournalJournal of medicinal chemistry (J Med Chem) Vol. 56 Issue 3 Pg. 902-14 (Feb 14 2013) ISSN: 1520-4804 [Electronic] United States
PMID23286881 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Chemical References
  • Cardiotonic Agents
  • Esters
  • Organophosphonates
  • Phosphates
  • Adenosine
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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