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10.1021/ml3003633 http://scihub22266oqcxt.onion/10.1021/ml3003633 C4027436!4027436!24900682     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       ACS+Med+Chem+Lett 2013 ; 4 (4): 381-6 Nephropedia Template TP {{tp|p=24900682|t=2013. Orally Active Fumagillin Analogues: Transformations of a Reactive Warhead in the Gastric Environment |pdf=|usr=}}{{24900682}} gab.com Text Orally Active Fumagillin Analogues: Transformations of a Reactive Warhead in the Gastric Environment JO: ACS Med Chem Lett http://www.kidney.de/pget.php?&tw=1&pmid=24900682 #FOAvip Semisynthetic analogues of fumagillin, 1, inhibit methionine aminopeptidase-2 (MetAP2) and have entered the clinic for the treatment of cancer. An optimized fumagillin analogue, 3 (PPI-2458), was found to be orally active, despite containing a spiroepoxide function that formed a covalent linkage to the target protein. In aqueous acid, 3 underwent ring-opening addition of water and HCl, leading to four products, 4?7, which were characterized in detail. The chlorohydrin, but not the diol, products inhibited MetAP2 under weakly basic conditions, suggesting reversion to epoxide as a step in the mechanism. In agreement, chlorohydrin 6 was shown to revert rapidly to 3 in rat plasma. In an ex vivo assay, rats treated with purified acid degradants demonstrated inhibition of MetAP2 that correlated with the biochemical activity of the compounds. Taken together, the results indicate that degradation of the parent compound was compensated by the formation of active equivalents leading to a pharmacologically useful level of MetAP2 inhibition. Twit Text FOAVip Orally Active Fumagillin Analogues: Transformations of a Reactive Warhead in the Gastric Environment ????ACS Med Chem Lett http://www.kidney.de/pget.php?&tw=1&pmid=24900682 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=24900682 #FOAvip English Wikipedia <ref>{{Cite pmid|24900682}}</ref> Orally Active Fumagillin Analogues: Transformations of a Reactive Warhead in the Gastric Environment #MMPMID24900682 Arico-Muendel CC; Blanchette H; Benjamin DR; Caiazzo T; Centrella PA; DeLorey J; Doyle EG; Johnson S; Labenski MT; Morgan BA; O?Donovan G; Sarjeant AA; Skinner S; Thompson CD; Griffin ST; Westlin W; White KF ACS Med Chem Lett 2013[Apr]; 4 (4): 381-6 PMID24900682show ga Semisynthetic analogues of fumagillin, 1, inhibit methionine aminopeptidase-2 (MetAP2) and have entered the clinic for the treatment of cancer. An optimized fumagillin analogue, 3 (PPI-2458), was found to be orally active, despite containing a spiroepoxide function that formed a covalent linkage to the target protein. In aqueous acid, 3 underwent ring-opening addition of water and HCl, leading to four products, 4?7, which were characterized in detail. The chlorohydrin, but not the diol, products inhibited MetAP2 under weakly basic conditions, suggesting reversion to epoxide as a step in the mechanism. In agreement, chlorohydrin 6 was shown to revert rapidly to 3 in rat plasma. In an ex vivo assay, rats treated with purified acid degradants demonstrated inhibition of MetAP2 that correlated with the biochemical activity of the compounds. Taken together, the results indicate that degradation of the parent compound was compensated by the formation of active equivalents leading to a pharmacologically useful level of MetAP2 inhibition. äOrally Active Fumagillin Analogues: Transformations of a Reactive Warh(epmc).pdf DeepDyve Pubget Overpricing