ABSTRACT
We demonstrate a general method for the preparation of diverse N-substituted 3,4-dihydroisoquinolin-1(2H)-one compounds through an overall three-step cross-coupling/cyclization/N-deprotection/N-alkylation sequence. In the first step, ethyl 2-bromobenzoates and 2-bromo-1-carboxyethyl heterocycles are cross-coupled with commercially available potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate to produce (hetero)aryl-substituted 3-[(N-Boc-2-carboxyethyl)phenyl]ethylamines. In a subsequent two-stage process, these (hetero)arylethylamines undergo base-mediated ring closure followed by N-deprotection and N-alkylation to produce N-substituted 3,4-dihydroisoquinolin-1(2H)-ones and heteroaryl-fused N-benzyl 3,4-dihydropyridin-2(1H)-ones. Mechanistic work was performed to elucidate the order of transformations for the latter two-stage process. The method was also extended to the production of N-benzyl isoindolin-1-one and N-benzyl 2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one.
ABSTRACT
The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aß42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aß42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aß42 levels in the plasma of J20 mice, in addition to reducing Aß42 levels in the plasma and brain of Tg2576 mice.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Pyridines/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/analysis , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/biosynthesis , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Female , Humans , Male , Mice , Mice, Transgenic , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a urea-thiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC50) concentration conferred by 1 is 3.2 µM with protection against 200 µM neomycin approaching 100%. Compound 1 was sufficiently safe and drug-like to validate otoprotection in an in vivo rat hearing loss model. We explored the structure-activity relationship (SAR) of this compound series to improve otoprotective potency, improve pharmacokinetic properties and eliminate off-target activity. We present the optimization of 1 to yield 90 (ORC-13661). Compound 90 protects mechanosensory hair cells with HC50 of 120 nM and demonstrates 100% protection in the zebrafish assay and superior physiochemical, pharmacokinetic, and toxicologic properties, as well as complete in vivo protection in rats.
Subject(s)
Aminoglycosides/adverse effects , Hearing Loss/chemically induced , Hearing Loss/prevention & control , Safety , Thiophenes/chemistry , Thiophenes/pharmacology , Urea/chemistry , Administration, Oral , Animals , Drug Evaluation, Preclinical , Rats , Structure-Activity Relationship , Thiophenes/administration & dosage , Thiophenes/adverse effects , ZebrafishABSTRACT
The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aß42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Drug Design , Thiazoles/chemistry , Amyloid Precursor Protein Secretases/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Half-Life , Humans , Kinetics , Male , Mice , Microsomes, Liver/metabolism , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Rats , Solubility , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacokineticsABSTRACT
IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity. Additionally, it was found that the pyrimidine core could be replaced with a pyridine and still retain potency and kinase selectivity. The optimization efforts led to compound 26 which had an IRAK4 IC50 of 0.7 nM, an IC50 of 55 nM on THP-1 cells stimulated with LPS, a TLR4 agonist, and greater than 100-fold selectivity versus 96% of a panel of 306 kinases.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cell Line , High-Throughput Screening Assays , Humans , Lipopolysaccharides/pharmacology , Structure-Activity Relationship , Substrate Specificity , Toll-Like Receptor 4/antagonists & inhibitorsABSTRACT
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 µM.
Subject(s)
Analgesics/pharmacology , Ganglia, Spinal/drug effects , NAV1.7 Voltage-Gated Sodium Channel/chemistry , Neuralgia/drug therapy , Sodium Channel Blockers/pharmacology , Spinal Nerves/drug effects , Spiro Compounds/pharmacology , Analgesics/chemistry , Animals , Molecular Structure , Patch-Clamp Techniques , Quinoxalines/chemistry , Rats , Sodium Channel Blockers/chemistry , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.
Subject(s)
Drug Discovery , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Quinoxalines/pharmacology , Sodium Channel Blockers/pharmacology , Spiro Compounds/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Structure , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Subject(s)
Antifungal Agents/chemistry , Enzyme Inhibitors/chemistry , Glucosyltransferases/antagonists & inhibitors , Pyridazines/chemistry , Sulfonamides/chemistry , Animals , Antifungal Agents/pharmacokinetics , Antifungal Agents/therapeutic use , Candida/drug effects , Candidiasis/drug therapy , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Glucosyltransferases/metabolism , Half-Life , Mice , Microbial Sensitivity Tests , Pyridazines/pharmacokinetics , Pyridazines/therapeutic use , Rats , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.
Subject(s)
Antifungal Agents/chemistry , Enzyme Inhibitors/chemistry , Glucosyltransferases/antagonists & inhibitors , Lead/chemistry , Piperazines/chemistry , Pyridazines/chemistry , Sulfonylurea Compounds/chemistry , Animals , Antifungal Agents/pharmacology , Candida/drug effects , Cell Line , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Piperazine , Pyridazines/pharmacology , Rats , Structure-Activity Relationship , Sulfonylurea Compounds/pharmacologyABSTRACT
The echinocandins are a class of semisynthetic natural products that target ß-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibited in vitro activity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GS in vitro, and there was a strong correlation between enzyme inhibition and in vitro antifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants of Saccharomyces cerevisiae with reduced susceptibility to the piperazinyl-pyridazinones had substitutions in FKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model of Candida glabrata infection.
Subject(s)
Antifungal Agents/pharmacology , Glucosyltransferases/antagonists & inhibitors , Animals , Antifungal Agents/chemistry , Candida glabrata/drug effects , Candida glabrata/enzymology , Candida glabrata/pathogenicity , Candidiasis/drug therapy , Male , Mice , Molecular Structure , Piperazines/chemistry , Piperazines/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/enzymologyABSTRACT
A novel series of pyridazinone analogs has been developed as potent ß-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glucosyltransferases/antagonists & inhibitors , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida albicans/drug effects , Candida glabrata/drug effects , Enzyme Inhibitors/chemistry , Molecular Structure , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
An enantiospecific and stereoselective total synthesis of the natural product (+)-crispine A has been demonstrated employing a Pictet-Spengler bis-cyclization reaction between commercially available (R)-(-)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate and 4-chloro-1,1-dimethoxybutane to preferentially provide the cis tricyclic adduct. Decarboxylation by a convenient two-step protocol provided the enantiopure natural product in three steps with an overall isolated yield of 32% from the amino acid. The unnatural antipode (-)-crispine A was similarly prepared in three steps from the commercially available (S)-(+)-amino acid.
Subject(s)
Isoquinolines/chemistry , Isoquinolines/chemical synthesis , Biological Products/chemical synthesis , Biological Products/chemistry , Stereoisomerism , Substrate Specificity , Tyrosine/chemistryABSTRACT
A simple protocol for the synthesis of Weinreb benzamides and alpha,beta-unsaturated Weinreb amides through a palladium-catalyzed cross-coupling reaction between organoboronic acids and N-methoxy-N-methylcarbamoyl chloride has been developed. The method is also applicable to the use of potassium organotrifluoroborates.
Subject(s)
Amides/chemistry , Boronic Acids/chemistry , Carbamates/chemistry , Alkenes/chemistry , Catalysis , Cyclization , Magnetic Resonance Spectroscopy , Molecular Structure , Palladium , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A total synthesis of the racemic natural product tylophorine [(+/-)-1] has been demonstrated using the palladium-catalyzed carboamination method developed by Wolfe and co-workers. In this case, an electron-rich aryl bromide 18 was prepared in four steps and subjected to palladium-catalyzed Wolfe carboamination conditions with olefinic carbamate 7 to provide the racemic 2-(arylmethyl)pyrrolidine (+/-)-19 in good yield and was further elaborated to racemic tylophorine. This application of the Wolfe carboamination protocol as a key step to construct a natural product provides further evidence of the utility of the method.
Subject(s)
Alkaloids/chemical synthesis , Antineoplastic Agents, Phytogenic/chemical synthesis , Carbamates/chemistry , Indolizines/chemical synthesis , Palladium/chemistry , Phenanthrenes/chemical synthesis , Alkaloids/chemistry , Alkenes/chemistry , Amination , Antineoplastic Agents, Phytogenic/chemistry , Catalysis , Hydrocarbons, Brominated/chemistry , Hydrocarbons, Cyclic/chemistry , Indolizines/chemistry , Models, Chemical , Phenanthrenes/chemistry , Pyrrolidines/chemistry , StereoisomerismABSTRACT
C-6 Biarylmethylamino purine derivatives of roscovitine (1) inhibit cyclin dependent kinases and demonstrate potent antiproliferative activity. Replacement of the aryl rings of the C-6 biarylmethylamino group with heterobiaryl rings has provided compounds with significantly improved activity. In particular, derivatives 18 g and 9 c demonstrated 1000-fold and 1250-fold improvements, respectively, in the growth inhibition of HeLa cells compared to roscovitine (1).
Subject(s)
Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Purines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Drug Design , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Purines/chemical synthesis , Purines/chemistry , Roscovitine , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A highly efficient procedure was developed for the microwave-assisted synthesis of N-heteroaryl-4-(2-chloroethyl)piperazines and N-heteroaryl-4-(2-chloroethyl)piperidines. Microwave irradiation of electron deficient heteroaryl chlorides with 1,4-diazabicyclo[2.2.2]octane (DABCO) at 160 degrees C for 15 min led to N-heteroaryl-4-(2-chloroethyl)piperazines in good to excellent yields. In a similar manner, microwave irradiation of electron deficient heteroaryl chlorides with quinuclidine at 180 degrees C for 15 min provided N-heteroaryl-4-(2-chloroethyl)piperidines in good to excellent yields. Extension of the method was demonstrated by the development of a one-pot, two-step microwave-assisted protocol for the synthesis of 4-(2-acetoxyethyl)-substituted N-heteroarylpiperazines and N-heteroarylpiperidines to demonstrate the production of a small library in a parallel fashion.
Subject(s)
Amines/chemistry , Chlorides/chemistry , Piperazines/chemical synthesis , Piperidines/chemical synthesis , Small Molecule Libraries/chemical synthesis , Amines/chemical synthesis , Chlorides/chemical synthesis , Microwaves , Piperazines/chemistry , Piperidines/chemistry , Quinuclidines/chemical synthesis , Quinuclidines/chemistry , Small Molecule Libraries/chemistry , Small Molecule Libraries/economicsABSTRACT
The synthesis of 3-pyridyl biaryl systems can be readily achieved by means of palladium-catalyzed Suzuki cross-coupling reactions between aryl halides and 3-pyridylboroxin. A series of cross-couplings were conducted in order to investigate the scope and limitations of this protocol.
ABSTRACT
A general synthetic approach to the isoprostanes has been established, based on intermolecular aldol condensation of a diazo ketone with an unsaturated aldehyde, followed by cyclization of the resulting diazo ketone to the cyclopropane. Subsequent kinetic opening with thiophenol followed by further elaboration then leads to the isoprostane. The history of this approach and the details of its development are discussed.
Subject(s)
Isoprostanes/chemical synthesis , Ketones/chemistry , Isoprostanes/chemistryABSTRACT
The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-d-Tic-d-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K(i) = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K(i) = 6600 nM). Sulfonamide 39 (K(i) = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K(i) = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K(i) = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.
Subject(s)
Piperazines/chemical synthesis , Receptor, Melanocortin, Type 4/agonists , Animals , Binding, Competitive , Biological Availability , Cell Line , Cyclic AMP/biosynthesis , Humans , Ligands , Piperazines/chemistry , Piperazines/pharmacology , Radioligand Assay , Rats , Rats, Inbred F344 , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
5-Substituted-1H-tetrazoles (RCN4H) are often used as metabolism-resistant isosteric replacements for carboxylic acids (RCO2H) in SAR-driven medicinal chemistry analogue syntheses. This review provides a brief summary of the medicinal chemistry of tetrazolic acids and highlights some examples of tetrazole-containing drug substances in the current literature. A survey of representative literature procedures for the preparation of 5-substituted-1H-tetrazoles, focusing on preparations from aryl and alkyl nitriles, is presented in sections by generalized synthetic methods.