ABSTRACT
Evaluation of kinetic parameters of drug-target binding, kon, koff, and residence time (RT), in addition to the traditional in vitro parameter of affinity is receiving increasing attention in the early stages of drug discovery. Target binding kinetics emerges as a meaningful concept for the evaluation of a ligand's duration of action and more generally drug efficacy and safety. We report the biological evaluation of a novel series of spirobenzo-oxazinepiperidinone derivatives as inhibitors of the human equilibrative nucleoside transporter 1 (hENT1, SLC29A1). The compounds were evaluated in radioligand binding experiments, i.e., displacement, competition association, and washout assays, to evaluate their affinity and binding kinetic parameters. We also linked these pharmacological parameters to the compounds' chemical characteristics, and learned that separate moieties of the molecules governed target affinity and binding kinetics. Among the 29 compounds tested, 28 stood out with high affinity and a long residence time of 87 min. These findings reveal the importance of supplementing affinity data with binding kinetics at transport proteins such as hENT1.
Subject(s)
Equilibrative Nucleoside Transporter 1 , Thioinosine , Humans , Biological Transport , Thioinosine/metabolism , Thioinosine/pharmacology , Equilibrative Nucleoside Transporter 1/chemistry , Equilibrative Nucleoside Transporter 1/metabolismABSTRACT
Protein arginine methyltransferase 5 (PRMT5) is an enzyme that can symmetrically dimethylate arginine residues in histones and nonhistone proteins by using S-adenosyl methionine (SAM) as the methyl donating cofactor. We have designed a library of SAM analogues and discovered potent, cell-active, and selective spiro diamines as inhibitors of the enzymatic function of PRMT5. Crystallographic studies confirmed a very interesting binding mode, involving protein flexibility, where both the cofactor pocket and part of substrate binding site are occupied by these inhibitors.
ABSTRACT
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Indoles/chemical synthesis , Drug Design , Humans , Structure-Activity RelationshipABSTRACT
The development of a general, mild, and functional-group-tolerant direct functionalization of N-heteroarenes by C-H functionalization with N-protected amines, including azetidines under Minisci-mediated photoredox conditions, is reported. A broad scope of substituted azetidines, including spirocyclic derivatives, and heterocycles were explored. This reaction enables the production of sp3-rich complex druglike structures in one step from unactivated feedstock amines and heterocycles.
ABSTRACT
An iron-catalyzed synthesis of sulfur- and sulfone-containing heterocycles is reported. The method is based on the cyclization of readily available substrates and proceeded with high efficiency and diastereoselectivity. A variety of sulfur-containing heterocycles bearing moieties suitable for subsequent functionalization are prepared. Illustrative examples of such postcyclization modifications are also presented.
ABSTRACT
An iron-catalyzed cyclization of hydroxy allylic derivatives into tetrahydropyrans possessing an N-heteroaryl at C2 is disclosed. The reaction proceeds with good yield and in high diastereoselectivity in favor of the more stable isomer. The diastereoselectivity results from an iron-induced reopening of the tetrahydropyrans, allowing a thermodynamic equilibration. The method allows access to a variety of 2,6-disubstituted as well as 2,4,6-trisubstituted tetrahydropyrans that could be considered as attractive scaffolds for the pharmaceutical industry.
ABSTRACT
The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aniline Compounds/chemistry , Triazoles/chemistry , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Aniline Compounds/chemical synthesis , Aniline Compounds/metabolism , Animals , Brain/metabolism , Drug Design , Humans , Mice , Mice, Transgenic , Protein Binding , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/metabolismABSTRACT
Two strategies, "hydrogenation-hydride reduction" and "quaternization-hydride reduction", are reported that make use of mild reaction conditions (room temperature) to efficiently remove the N-pyridin-2-yl directing group from a diverse set of C-2-substituted piperidines that were synthesized through directed Ru-catalyzed sp(3) C-H functionalization. The deprotected products are obtained in moderate to good overall yields irrespective of the strategy followed, indicating that both methods are generally equally effective. Only in the case of 2,6-disubstituted piperidines, could the "quaternization-hydride reduction" strategy not be used. The "hydrogenation-hydride reduction" protocol was successfully applied to trans- and cis-2-methyl-N-(pyridin-2-yl)-6-undecylpiperidine in a short synthetic route toward (±)-solenopsin A (trans diastereoisomer) and (±)-isosolenopsin A (cis diastereoisomer). The absolute configuration of the enantiomers of these fire ant alkaloids could be determined via VCD spectroscopy.
Subject(s)
Alkaloids/chemistry , Piperidines/chemistry , Pyridines/chemistry , Ruthenium/chemistry , Catalysis , Hydrogenation , Molecular Structure , StereoisomerismABSTRACT
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aß42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.
Subject(s)
Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Design , Piperidines/pharmacology , Triazoles/pharmacology , Alzheimer Disease/drug therapy , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Dogs , Humans , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperidines/chemistry , Piperidines/metabolism , Triazoles/chemistry , Triazoles/metabolismABSTRACT
Transition-metal-catalyzed sp(3) C-H activation has emerged as a powerful approach to functionalize saturated cyclic amines. Our group recently disclosed a direct catalytic arylation reaction of piperidines at the α position to the nitrogen atom. 1-(Pyridin-2-yl)piperidine could be smoothly α-arylated if treated with an arylboronic ester in the presence of a catalytic amount of [Ru3(CO)12] and one equivalent of 3-ethyl-3-pentanol. A systematic study on the substrate and reagent scope of this transformation is disclosed in this paper. The effect of substitution on both the piperidine ring and the arylboronic ester has been investigated. Smaller (pyrrolidine) and larger (azepane) saturated ring systems, as well as benzoannulated derivatives, were found to be compatible substrates with the α-arylation protocol. The successful use of a variety of heteroarylboronic esters as coupling partners further proved the power of this direct functionalization method. Mechanistic studies have allowed for a better understanding of the catalytic cycle of this remarkable transformation featuring an unprecedented direct transmetalation on a Ru(II)-H species.
Subject(s)
Amines/chemistry , Piperidines/chemistry , Pyridines/chemistry , Ruthenium/chemistry , Catalysis , Models, Molecular , Molecular StructureABSTRACT
The design and the synthesis of several chemical subclasses of imidazole containing γ-secretase modulators (GSMs) is described. Conformational restriction of pyridone 4 into bicyclic pyridone isosteres has led to compounds with high in vitro and in vivo potency. This has resulted in the identification of benzimidazole 44a as a GSM with low nanomolar potency in vitro. In mouse, rat, and dog, this compound displayed the typical γ-secretase modulatory profile by lowering Aß42 and Aß40 levels combined with an especially pronounced increase in Aß38 and Aß37 levels while leaving the total levels of amyloid peptides unchanged.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Benzimidazoles/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Imidazoles/chemical synthesis , Amyloid beta-Peptides/metabolism , Animals , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Benzoxazoles/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Dogs , Drug Design , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , Indazoles/pharmacology , Male , Mice , Microsomes, Liver/metabolism , Molecular Conformation , Peptide Fragments/metabolism , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1 antagonists, 4-phenyl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidin-5-one (1) was identified as a potent TRPA1 receptor antagonist. A series of analogous tricyclic 3,4-dihydropyrimidine-2-thiones has been prepared via the multi-component Biginelli reaction and subsequent derivatization. This has led to TRPA1 antagonists with potencies around 10nM for both rat and human derived TRPA1 receptors. The activity was shown to reside exclusively in the 4R-enantiomers.
Subject(s)
Nerve Tissue Proteins/antagonists & inhibitors , Pyrimidines/pharmacology , TRPC Cation Channels/antagonists & inhibitors , Thiones/pharmacology , Transient Receptor Potential Channels/antagonists & inhibitors , Animals , Calcium Channels , Humans , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , TRPA1 Cation Channel , Thiones/chemical synthesis , Thiones/chemistrySubject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Alzheimer Disease/enzymology , Amides/chemistry , Amides/pharmacology , Amides/therapeutic use , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/biosynthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Cinnamates/chemistry , Cinnamates/pharmacology , Cinnamates/therapeutic use , Clinical Trials as Topic , Ginsenosides/chemistry , Ginsenosides/pharmacology , Ginsenosides/therapeutic use , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , StereoisomerismABSTRACT
The TRPA1 channel can be considered as a key biological sensor to irritant chemicals. In this paper, the discovery of 11H-dibenz[b,e]azepines (morphanthridines) and dibenz[b,f][1,4]oxazepines is described as extremely potent agonists of the TRPA1 receptor. This has led to the discovery that most of the known tear gases are potent TRPA1 activators. The synthesis and biological activity of a number of substituted morphanthridines and dibenz[b,f][1,4]oxazepines have given insight into the SAR around this class of TRPA1 agonists, with EC(50) values ranging from 1 µM to 0.1 nM. Compounds 6 and 32 can be considered as the most potent TRPA1 agonists known to date, with 6 now being used successfully as a screening tool in the discovery of TRPA1 antagonists. The use of ligands such as 6 and 32 as pharmacological tools may contribute to the basic knowledge of the TRPA1 channel and advance the development of TRPA1 antagonists as potential treatment for conditions involving TRPA1 activation, including asthma and pain.
Subject(s)
Dibenzazepines/chemical synthesis , Dibenzoxazepines/chemical synthesis , Nerve Tissue Proteins/agonists , Oxazepines/chemical synthesis , Tear Gases/chemical synthesis , Transient Receptor Potential Channels/agonists , Calcium/metabolism , Calcium Channels , Cell Line , Dibenzazepines/chemistry , Dibenzazepines/pharmacology , Dibenzoxazepines/chemistry , Dibenzoxazepines/pharmacology , Fluorometry , Humans , Intracellular Space/metabolism , Ligands , Membrane Potentials/drug effects , Oxazepines/chemistry , Oxazepines/pharmacology , Patch-Clamp Techniques , Structure-Activity Relationship , TRPA1 Cation Channel , Tear Gases/chemistry , Tear Gases/pharmacologyABSTRACT
A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Models, Molecular , Quinazolines/chemical synthesis , Amyloid Precursor Protein Secretases/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Aspartic Acid Endopeptidases/chemistry , CHO Cells , Caco-2 Cells , Cell Membrane Permeability , Cricetinae , Cricetulus , Crystallography, X-Ray , Humans , Hydrogen Bonding , Molecular Conformation , Mutation , Oligopeptides/chemistry , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/blood , Peptide Fragments/metabolism , Quinazolines/chemistry , Quinazolines/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
REALISIS is a software system for reagent selection, library design, and profiling, developed to fit the workflow of bench chemists and medicinal chemists. Designed to be portable, the software offers a comprehensive graphical user interface and rapid, integrated functionalities required for reagent retrieval and filtering, product enumeration, and library profiling. REALISIS is component-based, consisting of four main modules: reagent searching; reagent filtering; library enumeration; and library profiling. Each module allows the chemist to access specific functionalities and diverse filtering and profiling mechanisms. By implementing the entire process of reagent selection, library design, and profiling and by integrating all the necessary functionalities for this process, REALISIS cuts the time required to design combinatorial and noncombinatorial libraries from several days to a few hours.