ABSTRACT
GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.
Subject(s)
Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Indazoles/chemistry , Indazoles/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Blood Glucose/analysis , Carboxylic Acids/pharmacokinetics , Humans , Indazoles/pharmacokinetics , Mice , Mice, Inbred C57BL , Models, MolecularABSTRACT
A novel type of hypervalent iodine(III) reagents, vinylbenziodoxolones (VBX), has been synthesized in a one-pot reaction from 2-iodobenzoic acid. VBX is bench stable, has been thoroughly characterized and the cyclic structure is supported by X-ray analysis. The reactivity of VBX was investigated in vinylation of nitrocyclohexane, and delivered vinylated products with opposite regioselectivity compared to acyclic vinyl(aryl)iodonium salts. The reagents could become a powerful tool in vinylation reactions under both metal-free and metal-catalyzed conditions.
ABSTRACT
Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.
Subject(s)
Epilepsy, Tonic-Clonic/prevention & control , Oxadiazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Receptors, G-Protein-Coupled/agonists , Animals , Diabetes Mellitus, Type 2/drug therapy , Dogs , Ether-A-Go-Go Potassium Channels/drug effects , Female , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Male , Mice, Inbred C57BL , Mice, Knockout , Oxadiazoles/chemistry , Oxadiazoles/therapeutic use , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Structure-Activity RelationshipABSTRACT
Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.
Subject(s)
Drug Inverse Agonism , Receptors, Ghrelin/agonists , Receptors, Ghrelin/antagonists & inhibitors , Urea/analogs & derivatives , Urea/pharmacology , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Receptors, Ghrelin/metabolism , Structure-Activity Relationship , Urea/chemistryABSTRACT
[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to naÑve, p<0.01) in plasma triacylglycerol (TAG) concentration.
Subject(s)
Acyltransferases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemistry , Acyltransferases/metabolism , Administration, Oral , Animals , Caco-2 Cells , Cell Membrane Permeability/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Half-Life , Humans , Mice , Nanostructures/chemistry , Povidone/chemistry , Structure-Activity Relationship , Triglycerides/metabolismABSTRACT
G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.
Subject(s)
Oxadiazoles/chemical synthesis , Pyridines/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Animals , Biological Availability , Carbamates/chemical synthesis , Carbamates/chemistry , Carbamates/pharmacology , Crystallography, X-Ray , Dogs , High-Throughput Screening Assays , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Molecular , Molecular Structure , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Small Molecule Libraries , Solubility , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The synthesis of the title salt, C(20)H(23)N(2)O(2) (+)·Cl(-), was carried out with a precursor of known absolute configuration (R) and the X-ray analysis confirmed that the product retained the absolute configuration. In the crystal, the dominant packing motif is a chain running along [010] generated by N-Hâ¯Cl hydrogen bonding. C-Hâ¯O and C-Hâ¯Cl inter-actions are also observed.
ABSTRACT
Cyclization reactions involving cyanoacetylated bisindoles have been studied, providing access to various novel cyclohepta[2,1-b:3,4-b']diindole derivatives as well as some related fused pentacyclic systems. Treatment of 3-cyanoacetyl-2,3'-diindolylmethane with methanesulfonic acid gave 6-(cyanomethyl)indolo[3,2-b]carbazole in a good yield.
Subject(s)
Aza Compounds/chemical synthesis , Carbazoles/chemical synthesis , Indoles/chemical synthesis , Acetylation , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, InfraredABSTRACT
Asymmetric oxidation of heterocyclic sulfides, including imidazole, benzimidazole, indole and pyrimidine derivatives, were studied using a tartrate/Ti((i)OPr)4 catalyst system.