ABSTRACT
AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.
Subject(s)
Oxadiazoles/chemistry , Pyridines/chemistry , Receptors, Metabotropic Glutamate/chemistry , Allosteric Regulation , Animals , Binding Sites , Central Nervous System/diagnostic imaging , Drug Evaluation, Preclinical , HEK293 Cells , Half-Life , Humans , Isotope Labeling , Male , Microsomes/metabolism , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Radionuclide Imaging , Rats , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity RelationshipABSTRACT
A series of potent antagonists of the ion channel transient receptor potential A1 (TRPA1) was developed by modifying lead structure 16 that was discovered by high-throughput screening. Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R(1) moiety and at the warhead, while the R(2) side had a much wider scope including ureas and carbamates. Compound 16 inhibits Ca(2+)-activated TRPA1 currents reversibly in whole cell patch clamp experiments, indicating that under in vivo conditions, it does not react covalently, despite its potentially electrophilic ketone.
Subject(s)
Amides/chemistry , Amides/pharmacology , Nerve Tissue Proteins/antagonists & inhibitors , Transient Receptor Potential Channels/antagonists & inhibitors , Calcium/metabolism , Calcium Channels/metabolism , Carbamates/chemistry , Carbamates/pharmacology , Humans , Nerve Tissue Proteins/metabolism , Patch-Clamp Techniques , Structure-Activity Relationship , TRPA1 Cation Channel , Transient Receptor Potential Channels/metabolism , Urea/chemistry , Urea/pharmacologyABSTRACT
The scope and limitation of the combined ruthenium-lipase induced dynamic kinetic resolution (DKR) through O-acetylation of racemic heteroaromatic secondary alcohols, i.e., 1-heteroaryl substituted ethanols, was investigated. After initial screening of reaction conditions, Candida antarctica lipase B (Novozyme 435, N435) together with 4-chloro-phenylacetate as acetyl-donor for kinetic resolution (KR), in conjunction with the ruthenium-based Shvo catalyst for substrate racemization in toluene at 80 degrees C, enabled DKR with high yields and stereoselectivity of various 1-heteroaryl ethanols, such as oxadiazoles, isoxazoles, 1H-pyrazole, or 1H-imidazole. In addition, DFT calculations based on a simplified catalyst complex model for the catalytic (de)hydrogenation step are in agreement with the previously reported outer sphere mechanism. These results support the further understanding of the mechanistic aspects behind the difference in reactivity of 1-heteroaryl substituted ethanols in comparison to reference substrates, as often referred to in the literature.
Subject(s)
Ethanol/analogs & derivatives , Ethanol/chemistry , Heterocyclic Compounds/chemistry , Lipase/metabolism , Ruthenium/chemistry , Biocatalysis , Enzymes, Immobilized , Ethanol/chemical synthesis , Ethanol/metabolism , Fungal Proteins , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/metabolism , Hydrogenation , Imidazoles/chemical synthesis , Imidazoles/chemistry , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Kinetics , Lipase/chemistry , Molecular Dynamics Simulation , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , StereoisomerismABSTRACT
Structure-activity relationship investigations of the thiopyrimidine (1), an HTS hit with micromolar activity as a metabotropic glutamate receptor 5 (mGluR5) antagonist, led to compounds with sub-micromolar activity.
