HIS-388, a novel orally active and long-acting 11ß-hydroxysteroid dehydrogenase type 1 inhibitor, ameliorates insulin sensitivity and glucose intolerance in diet-induced obesity and nongenetic type 2 diabetic murine models.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is considered a potential therapeutic target in the treatment of type 2 diabetes mellitus. In this study, we investigated the pharmacological properties of HIS-388 (N-[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]-3-(pyridin-2-yl) isoxazole-4-carboxamide), a newly synthesized 11ß-HSD1 inhibitor, using several mouse models. In cortisone pellet-implanted mice in which hypercortisolism and hyperinsulinemia occur, single administration of HIS-388 exhibited potent and prolonged suppression of plasma cortisol and lowered plasma insulin levels. These effects were more potent than those achieved using the same dose of other 11ß-HSD1 inhibitors (carbenoxolone and compound 544 [3-[(1s,3s)-adamantan-1-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine]), indicating that HIS-388 potently and continuously suppresses 11ß-HSD1 enzyme activity in vivo. In diet-induced obese mice, HIS-388 significantly decreased fasting blood glucose, plasma insulin concentration, and homeostasis model assessment-insulin resistance score, and ameliorated insulin sensitivity. In addition, HIS-388 significantly reduced body weight and suppressed the elevation of blood glucose during the pyruvate tolerance test. In nongenetic type 2 diabetic mice with disease induced by a high-fat diet and low-dose streptozotocin, HIS-388 also significantly decreased postprandial blood glucose and plasma insulin levels and improved glucose intolerance. The effects of HIS-388 on glucose metabolism were indistinguishable from those of an insulin sensitizer, pioglitazone. Our results suggest that HIS-388 is a potent agent against type 2 diabetes. Moreover, amelioration of diabetic symptoms by HIS-388 was at least in part attributable to an antiobesity effect or improvement of hepatic insulin resistance. Therefore, potent and long-lasting inhibition of 11ß-HSD1 enzyme activity may be an effective approach for the treatment of type 2 diabetes and obesity-associated disease.

Discovery of novel 7-membered cyclic amide derivatives that inhibit 11beta-hydroxysteroid dehydrogenase type 1.

A series of novel 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-ones that inhibit 11beta-hydroxysteroid dehydrogenase type 1 are described. We discovered these 7-membered cyclic amide derivatives by introducing a distinctive linker through pharmacophore analysis of known ligands included in X-ray co-crystal structures. Further optimization using docking studies led to highly potent inhibitors 15b and 27, which furthermore showed the potent efficacy in in vivo studies.

Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides as potent and selective dipeptidyl peptidase IV inhibitors.

A series of novel 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides were investigated as dipeptidyl peptidase IV (DPP-4) inhibitors. Introduction of a 4-phenylthiazol-2-yl group showed highly potent DPP-4 inhibitory activity. Among various derivatives, (3R)-3-amino-N-(4-(4-phenylthiazol-2-yl)-tetrahydro-2H-thiopyran-4-yl)-4-(2,4,5-trifluorophenyl)butanamide 1,1-dioxide (30) reduced blood glucose excursion in an oral glucose tolerance test by oral administration.

Pyrrolidinyl phenylurea derivatives as novel CCR3 antagonists.

Optimization starting with our lead compound 1 (IC(50)=4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC(50)=1.7 nM), a potent and orally active CCR3 antagonist.

Discovery and structure-activity relationships of urea derivatives as potent and novel CCR3 antagonists.

The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.

Discovery and structure-activity relationship of 2,6-disubstituted pyrazines, potent and selective inhibitors of protein kinase CK2.

We report the discovery and structure-activity relationship of 2,6-disubstituted pyrazines, which are potent and selective CK2 inhibitors. Lead compound 1 was identified, and derivatives were prepared to develop potent inhibitory activity. As a result, we obtained compound 7, which was the smallest unit that retained potency. Then, introducing an aminoalkyl group at the 6-position of the indazole ring resulted in improved efficacy in both enzymatic and cell-based CK2 inhibition assays. Moreover, compound 13 showed selectivity against other kinases and in vivo efficacy in a rat nephritis model. These results show that 2,6-disubstituted pyrazines have potential as therapeutic agents for nephritis.

Synthesis, biological evaluation, and metabolic stability of acrylamide derivatives as novel CCR3 antagonists.

Our laboratory has identified several acrylamide derivatives with potent CCR3 inhibitory activity. In the present study, we evaluated the in vitro metabolic stability (CL(int); mL/min/kg) of these compounds in human liver microsomes (HLMs), and assessed the relationship between their structures and CL(int) values. Among the compounds identified, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-[1-(2-hydroxybenzoyl)piperidin-4-ylidene]acetamide (30j) was found to be a potent inhibitor (IC(50)=8.4nM) with a high metabolic stability against HLMs.

(3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide as a potent dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides and 3-amino-N-(4-aryltetrahydropyran-4-yl)butanamides were synthesized and evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors. Derivatives incorporating the 6-substituted benzothiazole group showed highly potent DPP-IV inhibitory activity. Oral administration of (3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide (12u) reduced blood glucose excursion in an oral glucose tolerance test.

Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition.

In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using ClogD(7.4) values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC(50)=23 nM) with much reduced CYP2D6 inhibitory activity (IC(50)=29,000 nM) compared with 1.

Synthesis and structure-activity relationships of N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide derivatives as novel CCR3 antagonists.

A novel class of potent CCR3 receptor antagonists were designed and synthesized starting from N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide (1),which was found by subjecting our chemical library to high throughput screening (HTS). The CCR3 inhibitory activity of the synthesized compounds against eotaxin-induced Ca(2+) influx was evaluated using CCR3-expressing preB cells. Systematic chemical modifications of 1 revealed that the 6-fluoro-2-naphthylmethyl moiety was essential for CCR3 inhibitory activity in this new series of CCR3 antagonists. Further structural modifications of the benzamide and piperidine moieties of 1 led to the identification of exo-N-{8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3- yl}biphenyl-2-carboxamide [corrected] (31) as a potent CCR3 antagonist with an IC(50) value of 0.020 microM.