ABSTRACT
Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.
Subject(s)
Glycosides/chemistry , Hypoglycemic Agents/chemistry , Sodium-Glucose Transporter 2 Inhibitors , Spiro Compounds/chemistry , Animals , Cyclization , Glycosides/chemical synthesis , Glycosides/pharmacokinetics , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Male , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley , Sodium-Glucose Transporter 2/metabolismABSTRACT
Synthesis of a number of bicyclic five-membered ring derivatives of gabapentin led to the identification of two compounds, (-)-(11A) and (20A) which both had an excellent level of potency against alpha(2)delta and were profiled in an in vivo model of neuropathic pain.
Subject(s)
Amines/chemical synthesis , Amino Acids/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Cyclohexanecarboxylic Acids/chemical synthesis , gamma-Aminobutyric Acid/chemical synthesis , Amines/chemistry , Amines/pharmacokinetics , Amino Acids/chemistry , Amino Acids/pharmacokinetics , Animals , Blood-Brain Barrier/metabolism , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacokinetics , CHO Cells , Cricetinae , Cricetulus , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacokinetics , Gabapentin , Neuralgia/drug therapy , Pain Measurement , Rats , Stereoisomerism , Structure-Activity Relationship , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.
