Chapter 11. The Discovery and Development of MB07803, a Second-Generation Fructose-1,6-bisphosphatase Inhibitor with Improved Pharmacokinetic Properties, as a Potential Treatment of Type 2 Diabetes

Discovery of N-Arylsulfonyl-Indole-2-Carboxamide Derivatives as Potent, Selective, and Orally Bioavailable Fructose-1,6-Bisphosphatase Inhibitors—Design, Synthesis, In Vivo Glucose Lowering Effects, and X-ray Crystal Complex Analysis

“…Yellow solid; yield: 75%; mp >250 °C; 1 H-NMR (300 MHz, DMSO-d 6 ): δ (ppm) 12.67 (brs, 1H), 11.99 (s, 1H), 9.69 (s, 1H), 8.17 (d, J = 9.3 Hz, 1H), 7.98 (s, 1H), 7.36 (t, J = 8.1 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.93 (s, 1H), 6.81 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H), 3.43 (s, 3H); 13 C-NMR (150 MHz, DMSOd 6 ): δ (ppm) 160. 12, 158.31, 147.05, 140.39, 131.97, 130.27, 128.83, 127.23, 124.14, 116.79, 114.93, 110.63, 110.48, 108.43, 102.22, 55.17, 41.49 11, 158.00, 147.04, 140.38, 131.99, 130.26, 128.73, 127.21, 124.14, 116.80, 114.92, 110.62, 110.46, 108.41, 102.26, 55.17, 31.04, 5.69 11, 157.36, 147.09, 140.34, 139.29, 133.83, 132.01, 130.27, 129.20, 128.49, 127.69, 127.26, 124.10, 116.72, 114.98, 110.56, 110.51, 108.47, 102.27, 55.16 10, 159.15, 157.41, 147.07, 140.55, 140.33, 131.99, 130.49, 130.26, 128.55, 127.23, 124.09, 119.59, 119.45, 116.73, 114.96, 112.79, 110.49, 108.44, 102.27, 55.67, 55.16 (34). Yellow solid; yield: 55%; mp >250 °C; 1 H-NMR (400 MHz,: δ (ppm) 12.91 (brs,1H),11.85 (brs,1H),9.62 (brs,1H),8.13 (d,J = 9.2 Hz,1H),7.96 (d,J = 8.4 Hz,2H),7.82 (s,1H),7.33 (t,J = 8.0 Hz,1H),7.15 (d,J = 8.4 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 6.77 (t, J = 9.6 Hz, 2H), 3.85 (s, 3H), 3.76 (s, 3H); 13 C-NMR (100 MHz, DMSO-d 6 ): δ (ppm) 163.…”

“…32 The clinical trial of the first candidate CS-917 was terminated in 2008 because of the toxicity of its metabolite, and the second candidate MB07803 is now in phase II clinical trial. 33,34 Also, these two candidates bearing the phosphonic acid group were developed as phosphonic diamide prodrugs to achieve the oral bioavailability. Evidently, it is challenging to develop potent and orally bioavailable FBPase inhibitors without a phosphonic acid group.…”

“…Up to date, a number of FBPase inhibitors bearing distinct scaffolds have been identified via either high-throughput screening of compound libraries or structure-guided design of AMP mimetics. − At present, only two phosphonic acid-containing thiazole derivatives were advanced into clinical trials (Figure ). The clinical trial of the first candidate CS-917 was terminated in 2008 because of the toxicity of its metabolite, and the second candidate MB07803 is now in phase II clinical trial. , Also, these two candidates bearing the phosphonic acid group were developed as phosphonic diamide prodrugs to achieve the oral bioavailability. Evidently, it is challenging to develop potent and orally bioavailable FBPase inhibitors without a phosphonic acid group.…”

Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction

“…Moreover, many efforts have been made to discover inhibitors that bind to the AMP allosteric site of FBPase to treat T2D. − Among these inhibitors, MB06322 was tested in a phase II clinical trial for the treatment of T2D . However, it has been suggested that a metabolite (MB05099) of MB06322 (Figure S1) leads to lactic acidosis in humans. Additionally, a previous study , reported that the AMP site was a difficult target due to its high dependence on electrostatic binding interactions and lack of selectivity relative to other important enzymes involved in anabolic and catabolic pathways.…”