ABSTRACT
A new series of transient receptor potential vanilloid type 1 (TRPV1) antagonists were designed and synthesized from N-(3-hydroxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide hydrochloride (8). SAR studies identified (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide hydrochloride (ASP8370, 7), as a compound with high aqueous solubility, satisfactory stability in human liver microsomes, and reduced CYP3A4 inhibition. ASP8370 was selected as a clinical development candidate with significant ameliorative effects on neuropathic pain. SAR studies also revealed the structural mechanisms underlying the switching between TRPV1 antagonism and agonism.
Subject(s)
Amides/chemistry , Drug Design , TRPV Cation Channels/antagonists & inhibitors , Administration, Oral , Amides/metabolism , Amides/therapeutic use , Anticonvulsants/chemical synthesis , Anticonvulsants/metabolism , Anticonvulsants/therapeutic use , Biphenyl Compounds/chemistry , Cytochrome P-450 CYP3A/chemistry , Cytochrome P-450 CYP3A/metabolism , HEK293 Cells , Humans , Inhibitory Concentration 50 , Microsomes, Liver/metabolism , Neuralgia/drug therapy , Solubility , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucosides/chemistry , Glucosides/therapeutic use , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors , Animals , Azulenes/chemistry , Azulenes/therapeutic use , Blood Glucose/analysis , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/metabolism , Male , Mice , Rats , Rats, Sprague-Dawley , Sodium-Glucose Transporter 2/metabolismABSTRACT
A series of C-glucosides with various heteroaromatics has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compounds, the benzothiophene derivative (14a) was found to have potent inhibitory activity against SGLT2 and good selectivity versus SGLT1. Through further optimization of 14a, a novel benzothiophene derivative (14h; ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-A(y) mice and STZ rats.