ABSTRACT
A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11ß-HSD1. Among this series, 18e showed good in vitro activity toward human 11ß-HSD1, selectivity against 11ß-HSD2, microsomal stability, and pharmacokinetic and safety profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat and monkey models.
ABSTRACT
In the continuation of our 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor research, cyclic sulfonamide derivatives with an acetamide group at the 2-position were synthesized and evaluated for their abilities to inhibit 11ß-HSD1. Among this series, Compound 34 showed good in vitro activity toward human 11ß-HSD1, selectivity against 11ß-HSD2, microsomal stability, good pharmacokinetic and safety profiles human ether-a-go-go related gene (hERG and cytochrome P450 (CYP)). Also, a docking study explained the activity difference between human and mouse 11ß-HSD1.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Acetamides/chemistry , Enzyme Inhibitors/chemistry , Sulfonamides/chemistry , Thiazines/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Animals , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , ERG1 Potassium Channel , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Humans , MiceABSTRACT
A new series of thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their ability to inhibit 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1). Our initial compound 5a showed a weak inhibitory activity. Significant improvements in potency were achieved by substituent modification. The potent compound 8g (E) showed good in vitro inhibitory activity toward human 11ß-HSD1, selectivity toward 11ß-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this compound significantly inhibited 11ß-HSD1 activity in rat and monkey models, and showed improved glycemic control in KKAy mice.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Adamantane/chemistry , Enzyme Inhibitors/chemical synthesis , Thiazolidines/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Adamantane/chemical synthesis , Adamantane/pharmacokinetics , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Haplorhini , Humans , Mice , Microsomes, Liver/metabolism , Rats , Structure-Activity Relationship , Thiazolidines/chemical synthesis , Thiazolidines/pharmacokineticsABSTRACT
A new series of cyclic sulfonamide derivatives was synthesized and evaluated for their ability to inhibit 11beta-HSD1. Cyclic sulfonamides with phenylacetyl substituents at the 2-position showed nanomolar inhibitory activities. Among them, compound 4e exhibited a good in vitro inhibitory activity and selectivity toward human 11beta-HSD2.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Drug Discovery/methods , Sulfonamides/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Cell Line , Humans , Mice , Microsomes/drug effects , Microsomes/enzymology , Sulfonamides/metabolism , Sulfonamides/pharmacologyABSTRACT
A new synthetic small molecule, compound 1, which induced a neuronal differentiation from mesenchymal stem cells (MSCs) with an excellent efficiency, was identified. Furthermore the differentiated cell by 1 showed the neural electrophysiological and cholinergic neuron properties.
Subject(s)
Mesenchymal Stem Cells/drug effects , Neurons/drug effects , Animals , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Line , Electrophysiological Phenomena , Gene Expression Profiling , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/physiology , Neurons/cytology , Neurons/physiology , RatsABSTRACT
We report four cases in which a pericardium (Tutoplast) plug was used to repair a corneoscleral fistula after Ahmed Glaucoma Valve (AGV) explantation. In four cases in which the AGV tube had been exposed, AGV explantation was performed using a pericardium (Tutoplast) plug to seal the defect previously occupied by the tube. After debridement of the fistula, a piece of processed pericardium (Tutoplast), measured 1 mm in width, was plugged into the fistula and secured with two interrupted 10-0 nylon sutures. To control intraocular pressure, a new AGV was implanted elsewhere in case 1, phaco-trabeculectomy was performed concurrently in case 2, cyclophotocoagulation was performed postoperatively in case 3 and anti-glaucomatous medication was added in case 4. No complication related to the fistula developed at the latest follow-up (range: 12-26 months). The pericardium (Tutoplast) plug seems to be an effective method in the repair of corneoscleral fistulas resulting from explantation of glaucoma drainage implants.
