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

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 (C...