ABSTRACT
Group II metabotropic glutamate (mGlu) receptor agonists, including (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), have demonstrated efficacy in animal models of anxiety and schizophrenia, and LY354740 decreased anxiety in human subjects. Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of another potent, selective, and structurally novel mGlu2/3 receptor agonist, (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) and provide comparisons with LY354740. Similar to LY354740, LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors (K(i) = 149 and 92, respectively) and in rat neurons expressing native mGlu2/3 receptors (Ki = 88). LY404039 is highly selective for mGlu2/3 receptors, showing more than 100-fold selectivity for these receptors, versus ionotropic glutamate receptors, glutamate transporters, and other receptors targeted by known anxiolytic and antipsychotic medications. Functionally, LY404039 potently inhibited forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, and serotonin-induced l-glutamate release in the prefrontal cortex; effects reversed by LY341495. These characteristics suggest LY404039 modulates glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders; and that, similar to LY354740, it works through a mechanism that may be devoid of negative side effects associated with current antipsychotics and anxiolytics. Interestingly, despite the slightly lower potency (approximately 2-5-fold) of LY404039 versus LY354740 in binding, functional, and electrophysiological assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments. Collectively, the current data indicate that LY404039 may be valuable in the treatment of neuropsychiatric disorders, including anxiety and psychosis.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Cyclic S-Oxides/pharmacology , Cyclic S-Oxides/pharmacokinetics , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Agonists/pharmacokinetics , Receptors, Metabotropic Glutamate/drug effects , Animals , Binding Sites , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacokinetics , Bridged Bicyclo Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Cell Line , Cerebral Cortex/drug effects , Colforsin/pharmacology , Cyclic AMP/biosynthesis , Cyclic S-Oxides/chemistry , Electric Stimulation , Excitatory Amino Acid Agonists/chemistry , Excitatory Postsynaptic Potentials/drug effects , Humans , Hydrolysis , In Vitro Techniques , Male , Phosphatidylinositols/metabolism , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Serotonin/pharmacology , Serotonin Antagonists/pharmacologyABSTRACT
We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/drug therapy , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Binding Sites , Biological Availability , Collagen , Crystallography, X-Ray , Drug Design , Humans , Lipopolysaccharides/pharmacology , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Mice , Mice, Inbred BALB C , Mitogen-Activated Protein Kinase 14/chemistry , Models, Molecular , Rats , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.
