Discovery of Potent and Specific Fructose-1,6-Bisphosphatase Inhibitors and a Series of Orally-Bioavailable Phosphoramidase-Sensitive Prodrugs for the Treatment of Type 2 Diabetes

Abstract

Excessive glucose production by the liver coupled with decreased glucose uptake and metabolism by muscle, fat, and liver results in chronically elevated blood glucose levels in patients with type 2 diabetes. Efforts to treat diabetes by reducing glucose production have largely focused on the gluconeogenesis pathway and rate-limiting enzymes within this pathway such as fructose-1,6-bisphosphatase (FBPase). The first potent FBPase inhibitors were identified using a structure-guided drug design strategy (Erion, M. D.; et al. J. Am. Chem. Soc. 2007, 129, 15480-15490) but proved difficult to deliver orally. Herein, we report the synthesis and characterization of a series of orally bioavailable FBPase inhibitors identified following the combined discoveries of a low molecular weight inhibitor series with increased potency and a phosphonate prodrug class suitable for their oral delivery. The lead inhibitor, 10A, was designed with the aid of X-ray crystallography and molecular modeling to bind to the allosteric AMP binding site of FBPase. High potency (IC50 = 16 nM) and FBPase specificity were achieved by linking a 2-aminothiazole with a phosphonic acid. Free-energy perturbation calculations provided insight into the factors that contributed to the high binding affinity. 10A and standard phosphonate prodrugs of 10A exhibited poor oral bioavailability (0.2-11%). Improved oral bioavailability (22-47%) was achieved using phosphonate diamides that convert to the corresponding phosphonic acid by sequential action of an esterase and a phosphoramidase. Oral administration of the lead prodrug, MB06322 (30, CS-917), to Zucker Diabetic Fatty rats led to dose-dependent inhibition of gluconeogenesis and endogenous glucose production and consequently to significant blood glucose reduction.

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

“…# P!0.05 vs Veh/Ola; Z P!0.05 vs Met contributed to the decreased effect of the high Met dose on suppression of HGP following Ola during hyperinsulinemia. Interestingly, there are at least two in vivo studies, administering 300 mg/kg per day or 1000 mg/kg per day of Met in rodents, demonstrating respective increases in, or a lack of inhibition of HGP (Dang et al 2007, Yoshida et al 2009). It remains unclear why, contrary to our findings, Boyda et al (2012) found that both the 100 and 500 mg/kg Met doses significantly decreased glucose intolerance by Ola.…”

A Novel Type of Mono-Substituted Polyacetylene: Synthesis and Characterization of Poly(N-Propargylthiourea)s

“…They are extensively employed to synthesize functional drugs, well examplified by superior inhibitors of bacteria [4] and cancer [5]. Thioureas also have been used as intermediates for the synthesis of ureas, triazoles and thiazoles [6][7][8]. Their favorable metal-complexing ability made them widely used in metal extraction and metal detection [9,10].…”

Rational Design, Synthesis, and Potency of N‐Substituted Indoles, Pyrroles, and Triarylpyrazoles as Potential Fructose 1,6‐Bisphosphatase Inhibitors

“…Some of these compounds have excellent IC 50 values, such as MB05032 (IC 50 = 16 nm), [2] benzimidazole phosphonic acid (IC 50 = 90 nm), [3] and 10A (IC 50 = 16 nm). [4] Most drug candidates that reached early clinical trials were later determined to have serious toxic side effects or problems in delivery. [2][3][4] The therapeutic use of most drugs currently on the market (such as metformin and glibenclamide), is limited due to toxic side effects.…”

“…[4] Most drug candidates that reached early clinical trials were later determined to have serious toxic side effects or problems in delivery. [2][3][4] The therapeutic use of most drugs currently on the market (such as metformin and glibenclamide), is limited due to toxic side effects. [5][6][7] Therefore, the search for the ideal drug to ameliorate high blood glucose levels continues.…”

“…FBPase converts fructose 1,6-bisphosphate (FBP) into fructose 6-phosphate and inorganic phosphate; inhibition of this step along the gluconeogenesis pathway has been found to be effective in the control of blood sugar levels in rat models of the pre-diabetic state. [4,8] In a recent study [5] we synthesized and evaluated a broad group of compounds including substituted pyrazoles, pyrroles, indoles, and carbazoles for inhibition of FBPase in order to identify potential lead compounds that modulate the activity of this enzyme. Based on enzyme inhibition assays and docking studies we identified a small group of leads.…”