Discovery of a Series of Phosphonic Acid-Containing Thiazoles and Orally Bioavailable Diamide Prodrugs That Lower Glucose in Diabetic Animals Through Inhibition of Fructose-1,6-Bisphosphatase

Abstract

Oral delivery of previously disclosed purine and benzimidazole fructose-1,6-bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular weight (>600). Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach. The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration. Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%). Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM.

In Silico Identification of Structure Requirement for Novel Thiazole and Oxazole Derivatives as Potent Fructose 1,6-Bisphosphatase Inhibitors

“…A large, diverse dataset of 105 inhibitors of FBPase were collected from literatures [38,39] published by Dang and co-workers. Here, the converted molar pIC 50 (−log IC 50 ) values, ranging from 4.870 to 8.000 M, were used as the dependent variables in the QSAR regression analysis to improve the normal distribution of the experimental data points.…”

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…For example, compound 61 was prepared as an inhibitor of fructose 1,6-bisphosphatase [122]. The phosphonodiamidate prodrug was far more potent in human hepatocytes than the free acid and, after comparison with a broad range of other prodrugs, the bisamidate was judged superior and selected for clinical trials [123]. While Phase II trials with compound 61 ultimately proved disappointing, studies with second generation analogues continue [124].…”

Drug discovery for type 2 diabetes mellitus and metabolic syndrome: ten novel biological targets

“…Также остается проблемой селективное ингибирование печеночной изоформы фермента, которая имеет близкое строение с мышечной изоформой. При этом даже при заявленной селективно-сти соединения, второй серьезной проблемой ингибито-ров гликогенфосфорилазы является мышечная слабость и повышенная утомляемость, что у лиц с СД и ожире-нием ограничивает переносимость физических нагрузок, которые им крайне необходимы [25]. Важной проблемой данной группы препаратов являются возможные пато-морфологические изменения в печени вследствие на-копления в ней гликогена.…”