ABSTRACT
BACKGROUND: Mas-related G-protein coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell-mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo. OBJECTIVE: We identified and characterized novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell-mediated disease. METHODS: Antagonists were identified using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell-derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2em(-/-) knockout (KO) and Mrgprb2em(MRGPRX2) transgenic human MRGPRX2 knock-in (KI) mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. RESULTS: MRGPRX2 antagonists potently inhibited agonist-induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested, in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist-induced degranulation and resulting vascular permeability in MRGPRX2 KI mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin. CONCLUSION: MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.
ABSTRACT
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00481.].
ABSTRACT
Serine hydrolases are susceptible to potent reversible inhibition by boronic acids. Large collections of chemically diverse boronic acid fragments are commercially available because of their utility in coupling chemistry. We repurposed the approximately 650 boronic acid reagents in our collection as a directed fragment library targeting serine hydrolases and related enzymes. Highly efficient hits (LE > 0.6) often result. The utility of the approach is illustrated with the results against autotaxin, a phospholipase implicated in cardiovascular disease.
Subject(s)
Boronic Acids/chemistry , Phosphoric Diester Hydrolases/metabolism , Serine Proteinase Inhibitors/pharmacology , Small Molecule Libraries/pharmacology , Structure-Activity Relationship , Crystallography, X-Ray , Drug Evaluation, Preclinical/methods , Humans , Nitriles/chemistry , Phosphoric Diester Hydrolases/chemistry , Phosphoric Diester Hydrolases/genetics , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemistry , Small Molecule Libraries/chemistry , Surface Plasmon ResonanceABSTRACT
Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.
ABSTRACT
Cardiomyopathy is the leading cause of death worldwide. Despite progress in medical treatments, heart transplantation is one of the only current options for those with infarcted heart muscle. Stem cell differentiation technology may afford cell-based therapeutics that may lead to the generation of new, healthy heart muscle cells from undifferentiated stem cells. Our approach is to use small molecules to stimulate stem cell differentiation. Herein, we describe a novel class of 1,5-disubstituted benzimidazoles that induce differentiation of stem cells into cardiac cells. We report on the evaluation in vitro for cardiomyocyte differentiation and describe structure-activity relationship results that led to molecules with drug-like properties. The results of this study show the promise of small molecules to direct stem cell lineage commitment, to probe signaling pathways and to develop compounds for the stimulation of stem cells to repair damaged heart tissue.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Cell Differentiation/drug effects , Mouse Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/drug effects , Myocytes, Cardiac/cytology , Animals , Cells, Cultured , Mice , Myocytes, Cardiac/drug effects , Structure-Activity RelationshipABSTRACT
Catechol O-methyl transferase belongs to the diverse family of S-adenosyl-l-methionine transferases. It is a target involved in the treatment of Parkinson's disease. Here we present a fragment-based screening approach to discover noncatechol derived COMT inhibitors which bind at the SAM binding pocket. We describe the identification and characterization of a series of highly ligand efficient SAM competitive bisaryl fragments (LE = 0.33-0.58). We also present the first SAM-competitive small-molecule COMT co-complex crystal structure.
Subject(s)
Catechol O-Methyltransferase Inhibitors , S-Adenosylmethionine/metabolism , Animals , Binding Sites , Catechol O-Methyltransferase/chemistry , Humans , Kinetics , Mice , Models, Molecular , Protein Conformation , Pyrazoles/chemistry , Rats , S-Adenosylmethionine/chemistry , Structure-Activity Relationship , Thiazoles/chemistry , Triazoles/chemistryABSTRACT
A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor ß (TGFß)/Smad signaling by clearing the type II TGFß receptor from the cell surface. Because this is an unprecedented mechanism of action, we explored the series' structure-activity relationship (SAR) based on TGFß inhibition, and evaluated SAR aspects for cell-surface clearance of TGFß receptor II (TGFBR2) and for biological activity in mESCs. We determined a pharmacophore and generated 1,4-DHPs with IC(50)s for TGFß inhibition in the nanomolar range (e.g., compound 28, 170 nM). Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGFß inhibition for the (+)- than the (-) enantiomer. This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells.
Subject(s)
Cell Differentiation/drug effects , Dihydropyridines/pharmacology , Embryonic Stem Cells/drug effects , Myocytes, Cardiac/drug effects , Quinolones/pharmacology , Signal Transduction/drug effects , Small Molecule Libraries/pharmacology , Transforming Growth Factor beta/antagonists & inhibitors , Activins/antagonists & inhibitors , Activins/metabolism , Animals , Calcium/metabolism , Cells, Cultured , Dihydropyridines/chemical synthesis , Embryonic Stem Cells/cytology , Humans , Mice , Molecular Structure , Myocytes, Cardiac/cytology , Protein Binding , Protein Serine-Threonine Kinases/metabolism , Quinolones/chemical synthesis , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/metabolism , Stereoisomerism , Structure-Activity Relationship , Transforming Growth Factor beta/metabolismABSTRACT
The cellular signals controlling the formation of cardiomyocytes, vascular smooth muscle, and endothelial cells from stem cell-derived mesoderm are poorly understood. To identify these signals, a mouse embryonic stem cell (ESC)-based differentiation assay was screened against a small molecule library resulting in a 1,4-dihydropyridine inducer of type II TGF-ß receptor (TGFBR2) degradation-1 (ITD-1). ITD analogs enhanced proteasomal degradation of TGFBR2, effectively clearing the receptor from the cell surface and selectively inhibiting intracellular signaling (IC(50) ~0.4-0.8 µM). ITD-1 was used to evaluate TGF-ß involvement in mesoderm formation and cardiopoietic differentiation, which occur sequentially during early development, revealing an essential role in both processes in ESC cultures. ITD-1 selectively enhanced the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells. ITD-1 is a highly selective TGF-ß inhibitor and reveals an unexpected role for TGF-ß signaling in controlling cardiomyocyte differentiation from multipotent cardiovascular precursors.
Subject(s)
Dihydropyridines/pharmacology , Down-Regulation/drug effects , Embryonic Stem Cells/drug effects , Myocytes, Cardiac/drug effects , Protein Serine-Threonine Kinases/deficiency , Protein Serine-Threonine Kinases/metabolism , Proteolysis/drug effects , Receptors, Transforming Growth Factor beta/deficiency , Receptors, Transforming Growth Factor beta/metabolism , Animals , Cell Differentiation/drug effects , Cells, Cultured , Dihydropyridines/chemistry , Dose-Response Relationship, Drug , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Epidermal Growth Factor/deficiency , Epidermal Growth Factor/metabolism , HEK293 Cells , Humans , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/metabolism , Mice , Mice, Knockout , Molecular Weight , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Neoplasm Proteins/deficiency , Neoplasm Proteins/metabolism , Receptor, Transforming Growth Factor-beta Type II , Structure-Activity RelationshipABSTRACT
Human embryonic stem cell-based high-content screening of 550 known signal transduction modulators showed that one "lead" (1, a recently described inhibitor of the proteolytic degradation of Axin) stimulated cardiomyogenesis. Because Axin controls canonical Wnt signaling, we conducted an investigation to determine whether the cardiogenic activity of 1 is Wnt-dependent, and we developed a structure-activity relationship to optimize the cardiogenic properties of 1. We prepared analogues with a range of potencies (low nanomolar to inactive) for Wnt/ß-catenin inhibition and for cardiogenic induction. Both functional activities correlated positively (r(2) = 0.72). The optimal compounds induced cardiogenesis 1.5-fold greater than 1 at 30-fold lower concentrations. In contrast, no correlation was observed for cardiogenesis and modulation of transforming growth factor ß (TGFß)/Smad signaling that prominently influences cardiogenesis. Taken together, these data show that Wnt signaling inhibition is essential for cardiogenic activity and that the pathway can be targeted for the design of druglike cardiogenic molecules.
Subject(s)
Embryonic Stem Cells/drug effects , Heterocyclic Compounds, 3-Ring/chemical synthesis , Myocytes, Cardiac/drug effects , Tetrahydronaphthalenes/chemical synthesis , Wnt Proteins/antagonists & inhibitors , Cell Differentiation/drug effects , Cell Line , Embryonic Stem Cells/cytology , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Myocytes, Cardiac/cytology , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacologyABSTRACT
RATIONALE: Human embryonic stem cells can form cardiomyocytes when cultured under differentiation conditions. Although the initiating step of mesoderm formation is well characterized, the subsequent steps that promote for cardiac lineages are poorly understood and limit the yield of cardiomyocytes. OBJECTIVE: Our aim was to develop a human embryonic stem cell-based high-content screening assay to discover small molecules that drive cardiogenic differentiation after mesoderm is established to improve our understanding of the biology involved. Screening of libraries of small-molecule pathway modulators was predicted to provide insight into the cellular proteins and signaling pathways that control stem cell cardiogenesis. METHODS AND RESULTS: Approximately 550 known pathway modulators were screened in a high-content screening assay, with hits being called out by the appearance of a red fluorescent protein driven by the promoter of the cardiac-specific MYH6 gene. One potent small molecule was identified that inhibits transduction of the canonical Wnt response within the cell, which demonstrated that Wnt inhibition alone was sufficient to generate cardiomyocytes from human embryonic stem cell-derived mesoderm cells. Transcriptional profiling of inhibitor-treated compared with vehicle-treated samples further indicated that inhibition of Wnt does not induce other mesoderm lineages. Notably, several other Wnt inhibitors were very efficient in inducing cardiogenesis, including a molecule that prevents Wnts from being secreted by the cell, which confirmed that Wnt inhibition was the relevant biological activity. CONCLUSIONS: Pharmacological inhibition of Wnt signaling is sufficient to drive human mesoderm cells to form cardiomyocytes; this could yield novel tools for the benefit of pharmaceutical and clinical applications.
Subject(s)
Cell Differentiation/drug effects , Embryonic Stem Cells/drug effects , Mesoderm/drug effects , Myocytes, Cardiac/drug effects , Signal Transduction/drug effects , Wnt Proteins/antagonists & inhibitors , Cardiac Myosins/genetics , Cell Line , Dose-Response Relationship, Drug , Drug Discovery , Embryonic Stem Cells/metabolism , Gene Expression Profiling , Gene Expression Regulation, Developmental/drug effects , Genes, Reporter , High-Throughput Screening Assays , Humans , Luminescent Proteins/biosynthesis , Luminescent Proteins/genetics , Mesoderm/cytology , Mesoderm/metabolism , Microscopy, Fluorescence , Myocytes, Cardiac/metabolism , Myosin Heavy Chains/genetics , Promoter Regions, Genetic/drug effects , Small Molecule Libraries , Time Factors , Transfection , Wnt Proteins/metabolism , Red Fluorescent ProteinABSTRACT
Heart failure is one of the major causes of death in the Western world because cardiac muscle loss is largely irreversible and can lead to a relentless decline in cardiac function. Novel therapies are needed since the only therapy to effectively replace lost myocytes today is transplantation of the entire heart. The advent of embryonic and induced pluripotent stem cell (ESC/iPSC) technologies offers the unprecedented possibility of devising cell replacement therapies for numerous degenerative disorders. Not only are ESCs and iPSCs a plausible source of cardiomyocytes in vitro for transplantation, they are also useful tools to elucidate the biology of stem cells that reside in the adult heart and define signaling molecules that might enhance the limited regenerative capability of the adult human heart. Here, we review the extracellular factors that control stem cell cardiomyogenesis and describe new approaches that combine embryology with stem cell biology to discover drug-like small molecules that stimulate cardiogenesis and potentially contribute to the development of pharmaceutical strategies for heart muscle regeneration.
Subject(s)
Cardiovascular Agents/therapeutic use , Embryonic Stem Cells/drug effects , Heart Failure/drug therapy , Induced Pluripotent Stem Cells/drug effects , Myocytes, Cardiac/drug effects , Regeneration/drug effects , Animals , Cardiovascular Agents/chemistry , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Drug Design , Embryonic Stem Cells/metabolism , Embryonic Stem Cells/transplantation , Heart Failure/metabolism , Heart Failure/pathology , Heart Failure/physiopathology , Heart Failure/surgery , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/transplantation , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Myocytes, Cardiac/transplantation , Signal Transduction/drug effects , Stem Cell Transplantation , Treatment OutcomeABSTRACT
Antagonists of the corticotropin-releasing factor (CRF) neuropeptide may prove effective in treating stress and anxiety related disorders. In an effort to identify antagonists with improved physico-chemical properties a new series of CRF(1) antagonists were designed to substitute the propyl groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core of 1 with heterocycles. Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay.
Subject(s)
Azabicyclo Compounds/chemistry , Oxadiazoles/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Protein Binding , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Corticotropin-Releasing Hormone/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolismABSTRACT
Placental Alkaline Phosphatase (PLAP) is a tissue-restricted isozyme of the Alkaline Phosphatase (AP) superfamily. PLAP is an oncodevelopmental enzyme expressed during pregnancy and in a variety of human cancers, but its biological function remains unknown. We report here a series of catechol compounds with great affinity for the PLAP isozyme and significant selectivity over other members of the AP superfamily. These selective PLAP inhibitors will provide small molecule probes for the study of the pathophysiological role of PLAP.
Subject(s)
Alkaline Phosphatase/antagonists & inhibitors , Catechols/chemical synthesis , Catechols/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Isoenzymes/antagonists & inhibitors , Alkaline Phosphatase/metabolism , Catechols/chemistry , Enzyme Inhibitors/chemistry , GPI-Linked Proteins , Isoenzymes/metabolism , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA2A) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.
Subject(s)
Acetamides/therapeutic use , Adenosine A2 Receptor Antagonists , Pyrimidines/therapeutic use , Acetamides/chemical synthesis , Adenosine A1 Receptor Antagonists , Animals , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catalepsy/drug therapy , Drug Synergism , Haloperidol , Humans , Pyrimidines/chemical synthesis , Rats , Rotation , Solubility , Structure-Activity RelationshipABSTRACT
In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model.
Subject(s)
Adenosine A2 Receptor Antagonists , Aminopyridines/chemistry , Chemistry, Pharmaceutical/methods , Pyrimidines/chemical synthesis , Drug Design , Haloperidol/chemistry , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Models, Chemical , Parkinson Disease/therapy , Protein Binding , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor, Adenosine A1/chemistry , Receptor, Adenosine A2A/chemistry , Solubility , Structure-Activity RelationshipABSTRACT
4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA2A receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA2A Ki 2.3 nM, hA1 Ki 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA2A Ki 0.83 nM, hA1 Ki 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA2A Ki 0.44 nM, hA1 Ki 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation of l-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.
Subject(s)
Adenosine A2 Receptor Antagonists , Parkinson Disease/drug therapy , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Animals , Catalepsy/chemically induced , Catalepsy/drug therapy , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Haloperidol , Humans , Ligands , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Previously we have described a novel series of potent and selective A 2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A 2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.
Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Adenosine A2 Receptor Antagonists , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Acetamides/chemistry , Animals , Binding Sites , Cyclization , Drug Evaluation, Preclinical , Hepatocytes/drug effects , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Pyrimidines/chemistry , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.
Subject(s)
Acetamides/pharmacology , Adenosine A2 Receptor Antagonists , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Pyrimidines/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Adenosine A1 Receptor Antagonists , Animals , Drug Evaluation, Preclinical , Ether-A-Go-Go Potassium Channels/metabolism , Hepatocytes/drug effects , Humans , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Wistar , Species Specificity , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Antiparkinson Agents/chemical synthesis , Catalepsy/prevention & control , Parkinson Disease/physiopathology , Phenoxyacetates/chemical synthesis , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Antiparkinson Agents/pharmacology , Catalepsy/chemically induced , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2D6 Inhibitors , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Electrophysiology , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Haloperidol/toxicity , Humans , Molecular Structure , Phenoxyacetates/chemistry , Phenoxyacetates/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.