title: 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.
authors.affiliation: Molecular Recognition Section, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892, USA.
authors.forename: T Santhosh
authors.initials: TS
authors.lastname: Kumar
authors.forename: Tiehong
authors.initials: T
authors.lastname: Yang
authors.forename: Shilpi
authors.initials: S
authors.lastname: Mishra
authors.forename: Chunxia
authors.initials: C
authors.lastname: Cronin
authors.forename: Saibal
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Shen
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Liang
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004952:Esters; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D017202:Myocardial Ischemia / Q000517:prevention & control; D063065:Organophosphonates / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D002316:Cardiotonic Agents; D004952:Esters; D063065:Organophosphonates; D010710:Phosphates; D000241:Adenosine