Potent, selective, and orally available benzoisothiazolone phosphomannose isomerase inhibitors as probes for congenital disorder of glycosylation Ia

…, A Mangravita-Novo, L Yang, D Stonich…

Index: Dahl, Russell; Bravo, Yalda; Sharma, Vandana; Ichikawa, Mie; Dhanya, Raveendra-Panickar; Hedrick, Michael; Brown, Brock; Rascon, Justin; Vicchiarelli, Michael; Mangravita-Novo, Arianna; Yang, Li; Stonich, Derek; Su, Ying; Smith, Layton H.; Sergienko, Eduard; Freeze, Hudson H.; Cosford, Nicholas D. P. Journal of Medicinal Chemistry, 2011 , vol. 54, # 10 p. 3661 - 3668

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Citation Number: 27

Abstract

We report the discovery and validation of a series of benzoisothiazolones as potent inhibitors of phosphomannose isomerase (PMI), an enzyme that converts mannose-6- phosphate (Man-6-P) into fructose-6-phosphate (Fru-6-P) and, more importantly, competes with phosphomannomutase 2 (PMM2) for Man-6-P, diverting this substrate from critical protein glycosylation events. In congenital disorder of glycosylation type Ia, PMM2 activity ...