{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T10:34:50Z","timestamp":1760783690914,"version":"build-2065373602"},"reference-count":14,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2013,6,10]],"date-time":"2013-06-10T00:00:00Z","timestamp":1370822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A series of water\u2010soluble (benzoyloxy)methyl esters of acetylsalicylic acid (ASA), commonly known as aspirin, are described. The new derivatives each have alkyl chains containing a nitric oxide (NO)\u2010releasing nitrooxy group and a solubilizing moiety bonded to the benzoyl ring. The compounds were synthesized and evaluated as ASA prodrugs. After conversion to the appropriate salt, most of the derivatives are solid at room temperature and all possess good water solubility. They are quite stable in acid solution (pH\u20051) and less stable at physiological pH. In human serum, these compounds are immediately metabolized by esterases, producing a mixture of ASA, salicylic acid (SA), and of the related NO\u2010donor benzoic acids, along with other minor products. Due to ASA release, the prodrugs are capable of inhibiting collagen\u2010induced platelet aggregation of human platelet\u2010rich plasma. Simple NO\u2010donor benzoic acids 3\u2010hydroxy\u20104\u2010(3\u2010nitrooxypropoxy)benzoic acid (<jats:bold>28<\/jats:bold>) and 3\u2010(morpholin\u20104\u2010ylmethyl)\u20104\u2010[3\u2010(nitrooxy)propoxy]benzoic acid (<jats:bold>48<\/jats:bold>) were also studied as representative models of the whole class of benzoic acids formed following metabolism of the prodrugs in serum. These simplified derivatives did not trigger antiaggregatory activity when tested at 300\u2005\u03bc<jats:sc>M<\/jats:sc>. Only <jats:bold>28<\/jats:bold> displays quite potent NO\u2010dependent vasodilatatory action. Further in vivo evaluation of two selected prodrugs, {[2\u2010(acetyloxy)benzoyl]oxy}methyl\u20103\u2010[(3\u2010[aminopropanoyl)oxy]\u20104\u2010[3\u2010(nitrooxy)propoxy]benzoate\u22c5HCl (<jats:bold>38<\/jats:bold>) and {[2\u2010(acetyloxy)benzoyl]oxy}methyl 3\u2010(morpholin\u20104\u2010ylmethyl)\u20104\u2010[3\u2010(nitrooxy)propoxy]benzoate oxalate (<jats:bold>49<\/jats:bold>), revealed that their anti\u2010inflammatory activities are similar to that of ASA when tested in the carrageenan\u2010induced paw edema assay in rats. The gastrotoxicity of the two prodrugs was also determined to be lower than that of ASA in a lesion model in rats. Taken together, these results indicated that these NO\u2010donor ASA prodrugs warrant further investigation for clinical application.<\/jats:p>","DOI":"10.1002\/cmdc.201300105","type":"journal-article","created":{"date-parts":[[2013,6,10]],"date-time":"2013-06-10T15:32:18Z","timestamp":1370878338000},"page":"1199-1209","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Water\u2010Soluble Nitric\u2010Oxide\u2010Releasing Acetylsalicylic Acid (ASA) Prodrugs"],"prefix":"10.1002","volume":"8","author":[{"given":"Barbara","family":"Rolando","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loretta","family":"Lazzarato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Donnola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta","family":"Marini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sony","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppina","family":"Morini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Pozzoli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Fruttero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Gasco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,6,10]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389557013407160"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.10.6.911"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199906173402407"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar2465"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2009.05929.x"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.076190"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm020969t"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm701450q"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00123a040"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm900587h"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm2004514"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389557013407403"},{"key":"e_1_2_6_13_2","unstructured":"7\u2010Beta\u2010acylamido\u20103\u2010cephem\u20104\u2010carboxylic\u2010acid Esters Process for their Preparation Pharmaceutical Compositions and their Application B.Fechtig (Ciba\u2010Geigy Basel) European patent EP0136266 September 17 1984."},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja062948k"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcmdc.201300105","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.201300105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T21:59:56Z","timestamp":1760306396000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.201300105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,10]]},"references-count":14,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2013,7]]}},"alternative-id":["10.1002\/cmdc.201300105"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.201300105","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"type":"print","value":"1860-7179"},{"type":"electronic","value":"1860-7187"}],"subject":[],"published":{"date-parts":[[2013,6,10]]},"assertion":[{"value":"2013-03-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-06-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}