title: Potent, selective, and orally available benzoisothiazolone phosphomannose isomerase inhibitors as probes for congenital disorder of glycosylation Ia.
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 is compromised; thus, PMI inhibition is a potential strategy for the development of therapeutics. High-throughput screening (HTS) and subsequent chemical optimization led to the identification of a novel class of benzoisothiazolones as potent PMI inhibitors having little or no PMM2 inhibition. Two complementary synthetic routes were developed, enabling the critical structural requirements for activity to be determined, and the compounds were subsequently profiled in biochemical and cellular assays to assess efficacy. The most promising compounds were also profiled for bioavailability parameters, including metabolic stability, plasma stability, and permeability. The pharmacokinetic profile of a representative of this series (compound 19; ML089) was also assessed, demonstrating the potential of this series for in vivo efficacy when dosed orally in disease models.
authors.affiliation: Apoptosis and Cell Death Research Program, Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Yalda
authors.initials: Y
authors.lastname: Bravo
authors.forename: Vandana
authors.initials: V
authors.lastname: Sharma
authors.forename: Mie
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Raveendra-Panickar
authors.initials: RP
authors.lastname: Dhanya
authors.forename: Michael
authors.initials: M
authors.lastname: Hedrick
authors.forename: Brock
authors.initials: B
authors.lastname: Brown
authors.forename: Justin
authors.initials: J
authors.lastname: Rascon
authors.forename: Michael
authors.initials: M
authors.lastname: Vicchiarelli
authors.forename: Arianna
authors.initials: A
authors.lastname: Mangravita-Novo
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Derek
authors.initials: D
authors.lastname: Stonich
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D000284:Administration, Oral; D002626:Chemistry, Pharmaceutical / Q000379:methods; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D018981:Congenital Disorders of Glycosylation / Q000175:diagnosis* / Q000235:genetics; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008359:Mannose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D010539:Permeability; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D013844:Thiazoles; D008359:Mannose-6-Phosphate Isomerase