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: Russell Dahl, Yalda Bravo, Vandana Sharma, Mie Ichikawa, Raveendra-Panickar Dhanya, Michael Hedrick, Brock Brown, Justin Rascon, Michael Vicchiarelli, Arianna Mangravita-Novo, Li Yang, Derek Stonich, Ying Su, Layton H Smith, Eduard Sergienko, Hudson H Freeze, Nicholas D P Cosford
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 10 Pg. 3661-8 (May 26 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21539312 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Thiazoles
• Mannose-6-Phosphate Isomerase

Topics

• Administration, Oral
• Chemistry, Pharmaceutical (methods)
• Combinatorial Chemistry Techniques (methods)
• Congenital Disorders of Glycosylation (diagnosis, genetics)
• Drug Design
• Humans
• Inhibitory Concentration 50
• Mannose-6-Phosphate Isomerase (antagonists & inhibitors)
• Models, Chemical
• Permeability
• Structure-Activity Relationship
• Thiazoles (chemistry)