1215320-42-5Relevant articles and documents
Structure-activity relationship of (N)-methanocarba phosphonate analogues of 5′-AMP as cardioprotective agents acting through a cardiac P2X receptor
Santhosh Kumar,Zhou, Si-Yuan,Joshi, Bhalchandra V.,Balasubramanian, Ramachandran,Yang, Tiehong,Liang, Bruce T.,Jacobson, Kenneth A.
experimental part, p. 2562 - 2576 (2010/08/19)
P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y1 receptor). Two phosphonates,(1′S,2′R,3′S,4′R,5′S)- 4′-(6-amino-2-chloropurin-9-yl)-2′,3′-(dihydroxy) -1′-(phosphonomethylene)-bicyclo[3.1.0]hexane, 4 (MRS2775), and its homologue 9 (MRS2935), both 5′-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5′-extended phosphonates, all 2-H analogues, and a CH3-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure.
