Asymmetric Cycloaddition Reactions of Aryne Intermediates with a Chiral Carbon-Carbon Axis: Syntheses of Axially Chiral Biaryl Compounds.

An asymmetric synthesis via an axially chiral arylaryne intermediate was developed. A cycloaddition reaction with various arynophiles was used to obtain chiral biaryl compounds while preserving the enantiomeric excess (ee) of a precursor even though the reaction proceeds through an arylaryne intermediate, whose ee decreases on a time-dependent basis. High chiral transfer from a precursor to a product was observed not only at low temperature (-78 °C) but also at room temperature.

Synthesis and evaluation of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety as selective ß3-adrenergic receptor agonists.

In the search for potent and selective human ß3-adrenergic receptor (AR) agonists as potential drugs for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety were prepared and their biological activities against human ß3-, ß2-, and ß1-ARs were evaluated. Among these compounds, N-phenyl-(2-phenylaminothiazol-4-yl)acetamide (4 g), N-phenyl-(2-benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3-methoxyphenyl)aminothiazol-4-yl]acetamide (6g) derivatives showed potent agonistic activity against the ß3-AR with functional selectivity over the ß1- and ß2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent model of diabetes.

Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells.

Oxidative stress is widely recognized as being associated with a number of disorders, including metabolic dysfunction and atherosclerosis. A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). One compound in particular, 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one (25b), inhibited ROS production from HUVECs with an IC(50) of 140 nM. This compound also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.

Synthesis and evaluation of novel phenylethanolamine derivatives containing acetanilides as potent and selective beta3-adrenergic receptor agonists.

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential pharmacotherapies for the treatment of obesity and non-insulin dependent (type II) diabetes, we prepared a novel series of phenylethanolamine derivatives containing acetanilides and evaluated their biological activities at the human beta3-, beta2-, and beta1-ARs. Among these compounds, the 6-amino-2-pyridylacetanilide (36b), 2-amino-5-methylthiazol-4-ylacetanilide (36g), and 5-amino-1,2,4-thiadiazol-3-ylacetanilide (36h) derivatives showed potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent diabetic model.

Discovery of novel thiourea derivatives as potent and selective beta3-adrenergic receptor agonists.

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, we prepared a novel series of phenoxypropanolamine derivatives containing the thiourea moiety and evaluated their biological activities at human beta3-, beta2-, and beta1-ARs. Among these compounds, 4-nitrophenylthiourea (18i) and 3-methoxyphenylthiourea (18k) derivatives were found to exhibit potent agonistic activity at the beta3-AR, with EC(50) values of 0.10 and 0.16 microM, respectively, and no agonistic activity for either the beta1- or beta2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.

Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective beta3-adrenergic receptor agonists.

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the beta3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective beta3-AR agonist, with an EC(50) value of 0.28 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.

Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.

Design, synthesis, and pharmacological evaluation of N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives as potent glycogen phosphorylase inhibitors.

As a result of the various N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives with a hydroxy moiety synthesized in an effort to discover novel glycogen phosphorylase (GP) inhibitors, 5-chloro-N-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (5b) was found to have potent inhibitory activity. The introduction of fluorine atoms both at a position adjacent to the hydroxy group and in the central benzene moiety lead to the optically active derivative 5-chloro-N-[(5R)-1,3,6,6-tetrafluoro-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1H-indole-2-carboxamide (25e(alpha), which was the most potent compound in this series (IC(50)=0.020microM). This compound inhibited glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) value of 0.69microM, and showed oral hypoglycemic activity in diabetic db/db mice at 10mg/kg. Compound 25e(alpha) also had an excellent pharmacokinetic profile, with high oral bioavailability and a long plasma half-life, in male SD rats. The binding mode of 25e(alpha) to this molecule and the role of fluorine atoms in that binding were speculated in an enzyme docking study.

Synthesis and pharmacological evaluation of bis-3-(3,4-dichlorophenyl)acrylamide derivatives as glycogen phosphorylase inhibitors.

During our research using a high-throughput screening system for discovery of a new class of human liver glycogen phosphorylase a (hLGPa) inhibitors, a series of 3-(3,4-dichlorophenyl)acrylamide derivatives were synthesized, and their inhibitory activities toward hLGPa were evaluated. Among the derivatives, (2E,2'E)-N,N'-pentane-1,5-diylbis[3-(3,4-dichlorophenyl)acrylamide] (6c) inhibited hLGPa with an IC(50) value of 0.023 microM. An X-ray crystallographic study of the enzyme-6c complex showed that the inhibitor is bound at the dimer interface site, where the 3,4-dichlorophenyl moiety interacts hydrophobically with the enzyme.

Synthesis of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives as inhibitors of human liver glycogen phosphorylase a.

A series of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives were prepared and evaluated as inhibitors of human liver glycogen phosphorylase a (hLGPa). One compound, 5-chloro-N-[4-(1,2-dihydroxyethyl)phenyl]-1H-indole-2-carboxamide (2f), inhibited hLGPa with an IC(50) of 0.90microM. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) of 0.62microM and oral hypoglycemic activity in diabetic db/db mice. Crystallographic determination of the complex of 2f with hLGPa showed binding of the inhibitor in a solvent cavity at the dimer interface, with the two hydroxyl groups making favorable electrostatic interactions with hLGPa.