5鈥?Phosphate and 5鈥?Phosphonate Ester Derivatives of (N)-Methanocarba Adenosine with in Vivo Cardioprotective Activity

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• 作者：T. Santhosh Kumar ; Tiehong Yang ; Shilpi Mishra ; Chunxia Cronin ; Saibal Chakraborty ; Jian-Bing Shen ; Bruce T. Liang ; Kenneth A. Jacobson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：902-914
• 全文大小：468K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

Activation of a cardiac myocyte P2X4 receptor protects against heart failure. 5鈥?Phosphonate and 5鈥?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鈥?i>S,2鈥?i>R,3鈥?i>S,4鈥?i>R,5鈥?i>S)-4鈥?(6-amino-2-chloropurin-9-yl)-2鈥?3鈥?(dihydroxy)-1鈥?(phosphonoethylene)bicyclo[3.1.0]hexane was highly efficacious (CSQ), while lower homologue 1鈥?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.