ABSTRACT
We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0.3mg/kg, q.d.).
Subject(s)
Antidepressive Agents/pharmacology , Pyridines/pharmacology , Receptor, Metabotropic Glutamate 5/antagonists & inhibitors , Administration, Oral , Allosteric Regulation/drug effects , Animals , Antidepressive Agents/administration & dosage , Antidepressive Agents/chemistry , Behavior, Animal/drug effects , Dose-Response Relationship, Drug , Molecular Structure , Motor Activity/drug effects , Pyridines/administration & dosage , Pyridines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
The design, synthesis and SAR studies of novel 4,5,6,7-tetrahydropyrazolopyrazines as metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) are presented in this letter. Starting from a HTS hit compound (1, IC50=477nM), optimization of various groups led to the synthesis of a potent mGluR5 NAM (32, IC50=75nM) with excellent rat PK profile and good brain penetration. This compound produced oral antidepressant-like effect in a mouse tale suspension model (MED: 30mg/kg).
Subject(s)
Antidepressive Agents/chemical synthesis , Pyrazines/chemical synthesis , Pyrazoles/chemical synthesis , Pyridines/chemistry , Receptor, Metabotropic Glutamate 5/metabolism , Allosteric Regulation , Animals , Antidepressive Agents/metabolism , Antidepressive Agents/therapeutic use , Brain/metabolism , Depression/drug therapy , Disease Models, Animal , Half-Life , Humans , Mice , Microsomes, Liver/metabolism , Protein Binding , Pyrazines/chemistry , Pyrazines/pharmacokinetics , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Receptor, Metabotropic Glutamate 5/chemistry , Structure-Activity RelationshipABSTRACT
The continued SAR investigation of tryptamine-based human beta(3)-adrenergic receptor (AR) agonists is reported. Prior efforts resulted in the identification of 2 as a potent beta(3)-AR agonist. Further modification of the left side arylsulfonamide portion in 2 provided compounds with good cell permeability, which have potent agonistic activity for beta(3)-AR. Cinnamylamine analog 16i exhibited an excellent agonistic profile in vitro and good oral bioavailability in rats.
Subject(s)
Adrenergic Agonists/chemical synthesis , Adrenergic Agonists/pharmacokinetics , Receptors, Adrenergic, beta-3/metabolism , Sulfonamides/chemical synthesis , Tryptamines , Administration, Oral , Adrenergic Agonists/pharmacology , Biological Availability , Cell Membrane Permeability , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacologyABSTRACT
We have previously reported that (4R,5R)-5-ethyl-2-imino-4-methylthiazolidine (3) strongly inhibits inducible nitric oxide synthase (iNOS). In a successive search for strong and selective iNOS inhibitors, we, herein, describe the synthesis of the selenium analogue of 3 (4: ES-2133) and its related optically active compounds and examine their in vitro and in vivo inhibitory activity against iNOS. In addition, an alternative synthetic method to the selected compound 4 and its pharmacokinetic profile is also reported.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Nitric Oxide Synthase/antagonists & inhibitors , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/pharmacokinetics , Arginine/antagonists & inhibitors , Biological Availability , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Kinetics , Molecular Conformation , Nitric Oxide Synthase Type II , Organoselenium Compounds/chemistry , Selenium/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis and evaluation of a novel series of 1,7-cyclized indole-based human adrenergic receptor (beta3-AR) agonists are reported. The synthesis of a variety of 1,7-cyclized indole part was accomplished by the Mitsunobu reaction or a ring closing metathesis (RCM) reaction. SAR studies revealed that expansion of the ring size resulted in considerable selectivity against the beta1- and beta2-ARs. Compound 26, an eight-membered ring analogue with a double bond on its 1,7-linker portion, was found to be a potent beta3-AR agonist (EC50 = 0.75 nM, IA = 90%) with extremely high selectivity for the beta3-AR over the beta1- and beta2-ARs.
