ABSTRACT
Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington's disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR-/- mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/etiology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Quinolones/pharmacology , Receptors, Aryl Hydrocarbon/agonists , Receptors, Aryl Hydrocarbon/metabolism , Animals , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A1/metabolism , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Gene Deletion , Gene Expression , Gene Expression Profiling , Gene Expression Regulation/drug effects , Hepatocytes/metabolism , Humans , Immune System/immunology , Immune System/metabolism , Mice , Mice, Knockout , Receptors, Aryl Hydrocarbon/genetics , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , TranscriptomeABSTRACT
The diastereoselective synthesis and biological activity of piperidine-3,4-diol and piperidine-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3,4-diol and piperidine-3-ol derivatives showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochemical and pharmacokinetic properties. Furthermore, the stereochemistry of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation. Thus, trans-4-aryl-piperidine-3-ols (22) were more potent than the cis diastereomers (20).
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Lymphoma, Large-Cell, Anaplastic/drug therapy , Pyrroles/chemistry , Pyrroles/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Triazines/chemistry , Triazines/therapeutic use , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Crystallography, X-Ray , Humans , Lymphoma, Large-Cell, Anaplastic/enzymology , Mice, SCID , Models, Molecular , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrroles/pharmacokinetics , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/metabolism , Triazines/pharmacokineticsABSTRACT
Accumulating evidence suggests that autoreactive plasma cells play an important role in systemic lupus erythematosus (SLE). In addition, several proinflammatory cytokines promote autoreactive B cell maturation and autoantibody production. Hence, therapeutic targeting of such cytokine pathways using a selective JAK2 inhibitor, CEP-33779 (JAK2 enzyme IC(50) = 1.3 nM; JAK3 enzyme IC(50)/JAK2 enzyme IC(50) = 65-fold), was tested in two mouse models of SLE. Age-matched, MRL/lpr or BWF1 mice with established SLE or lupus nephritis, respectively, were treated orally with CEP-33779 at 30 mg/kg (MRL/lpr), 55 mg/kg or 100 mg/kg (MRL/lpr and BWF1). Studies included reference standard, dexamethasone (1.5 mg/kg; MRL/lpr), and cyclophosphamide (50 mg/kg; MRL/lpr and BWF1). Treatment with CEP-33779 extended survival and reduced splenomegaly/lymphomegaly. Several serum cytokines were significantly decreased upon treatment including IL-12, IL-17A, IFN-α, IL-1ß, and TNF-α. Anti-nuclear Abs and frequencies of autoantigen-specific, Ab-secreting cells declined upon CEP-33779 treatment. Increased serum complement levels were associated with reduced renal JAK2 activity, histopathology, and spleen CD138(+) plasma cells. The selective JAK2 inhibitor CEP-33779 was able to mitigate several immune parameters associated with SLE advancement, including the protection and treatment of mice with lupus nephritis. These data support the possibility of using potent, orally active, small-molecule inhibitors of JAK2 to treat the debilitative disease SLE.
Subject(s)
Enzyme Inhibitors/therapeutic use , Janus Kinase 2/antagonists & inhibitors , Lupus Nephritis/drug therapy , Plasma Cells/drug effects , Pyridines/therapeutic use , Triazoles/therapeutic use , Administration, Oral , Animals , Antibodies, Antinuclear/blood , Autoimmunity/drug effects , Autoimmunity/immunology , Cell Separation , Cytokines/blood , Disease Models, Animal , Enzyme Inhibitors/pharmacokinetics , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Lupus Nephritis/immunology , Lupus Nephritis/pathology , Mice , Mice, Inbred MRL lpr , Plasma Cells/immunology , Pyridines/pharmacokinetics , Triazoles/pharmacokineticsABSTRACT
CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H3 receptor (H3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (K(i) = 2.7 ± 0.3 nM) and recombinant rat and human H3R-expressing systems (K(i) = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [³5S]guanosine 5'-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H3R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC50 = 0.1 ± 0.003 mg/kg), and antagonism of the H3R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50 = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.
Subject(s)
Cognition/drug effects , Histamine H3 Antagonists/pharmacology , Nootropic Agents , Pyridazines/pharmacology , Pyrrolidines/pharmacology , Wakefulness/drug effects , Animals , Autoradiography , Behavior, Animal/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Dose-Response Relationship, Drug , Drinking/drug effects , Electroencephalography/drug effects , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Male , Memory, Short-Term/drug effects , Radioligand Assay , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Recognition, Psychology/drug effects , Reflex, Startle/drug effects , Sleep/drug effects , Social BehaviorABSTRACT
Synthesis and activity of a series of 3-aroyl-derived analogs of novel pyrrolocarbazole 1 as poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors are disclosed.
Subject(s)
Enzyme Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Antineoplastic Agents/pharmacology , Carbazoles/chemistry , Chemistry, Pharmaceutical/methods , DNA Damage , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , NAD/chemistry , Neoplasms/drug therapy , PC12 Cells , Poly (ADP-Ribose) Polymerase-1 , RatsABSTRACT
Among its various catalytic activities, the 'chymotrypsin-like' activity of the proteasome, a large multicatalytic proteinase complex has emerged as the focus of drug discovery efforts in cancer therapy. Herein, a series of first generation (2S, 3R)-2-amino-3-hydroxybutyric acid derived proteasome inhibitors that were discovered serendipitously en route to original goal of generating a series of sterically constrained oxazoline derivatives has been reported.
Subject(s)
Enzyme Inhibitors/pharmacology , Proteasome InhibitorsABSTRACT
In search of a next generation molecule to modafinil, a novel wake promoting agent, we previously disclosed bi-phenyl derived racemate compound (±)-2 as a new generation of wake-promoting agent. Here we describe the profiles of the individual enantiomers (-)-2 and (+)-2, respectively.
Subject(s)
Biphenyl Compounds/chemical synthesis , Central Nervous System Stimulants/chemical synthesis , Wakefulness/drug effects , Animals , Area Under Curve , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Central Nervous System Stimulants/pharmacokinetics , Central Nervous System Stimulants/pharmacology , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Electroencephalography , Injections, Intraperitoneal , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Retinoic Acid 4-Hydroxylase , Sleep/drug effects , Stereoisomerism , Structure-Activity Relationship , Wakefulness/physiologyABSTRACT
In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.
Subject(s)
Benzhydryl Compounds/chemical synthesis , Biphenyl Compounds/chemical synthesis , Central Nervous System Stimulants/chemical synthesis , Wakefulness/drug effects , Animals , Area Under Curve , Benzhydryl Compounds/pharmacokinetics , Benzhydryl Compounds/pharmacology , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Central Nervous System Stimulants/pharmacokinetics , Central Nervous System Stimulants/pharmacology , Electroencephalography , Injections, Intraperitoneal , Male , Modafinil , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Sleep/drug effects , Stereoisomerism , Structure-Activity Relationship , Wakefulness/physiologyABSTRACT
In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an active metabolite (compound 3).
Subject(s)
Benzhydryl Compounds/chemistry , Fluorenes/chemistry , Neuroprotective Agents/chemistry , Sulfoxides/chemistry , Animals , Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/pharmacokinetics , Brain/drug effects , Brain/metabolism , Fluorenes/chemical synthesis , Fluorenes/pharmacokinetics , Injections, Intraperitoneal , Modafinil , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacokinetics , Rats , Sulfoxides/chemical synthesis , Sulfoxides/pharmacokineticsABSTRACT
Proteasome, a large multicatalytic proteinase complex that plays an important role in processing of proteins, has been shown to possess multiple catalytic activities. Among its various activities, the 'chymotrypsin-like' activity of proteasome has emerged as the focus of drug discovery efforts in cancer therapy. Herein we report chiral boronate derived novel, potent, selective and cell-permeable peptidomimetic inhibitors 6 and 7 that displayed activity against various rodent and human tumor cell lines (in vitro).
Subject(s)
Boronic Acids/chemistry , Nitro Compounds/chemistry , Protease Inhibitors/chemistry , Proteasome Inhibitors , Animals , Boronic Acids/pharmacology , Boronic Acids/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Liver/enzymology , Mice , Neoplasms/drug therapy , Nitro Compounds/pharmacology , Nitro Compounds/therapeutic use , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Proteasome Endopeptidase Complex/metabolismABSTRACT
A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure-activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product-derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.
Subject(s)
Receptors, Calcitonin Gene-Related Peptide , Receptors, G-Protein-Coupled , Calcitonin Receptor-Like Protein/chemistry , Calcitonin Receptor-Like Protein/metabolism , Crystallography, X-Ray , Ligands , Receptors, Calcitonin Gene-Related Peptide/chemistry , Receptors, Calcitonin Gene-Related Peptide/metabolism , Receptors, G-Protein-Coupled/metabolismABSTRACT
There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone.
Subject(s)
Chemistry, Pharmaceutical , Glutathione/metabolism , Microsomes, Liver/enzymology , Protein Kinase Inhibitors/metabolism , Pyrroles/metabolism , Triazines/metabolism , Animals , Bile/chemistry , Biotransformation , Chromans/metabolism , Chromatography, High Pressure Liquid , Chromatography, Liquid , Clozapine/metabolism , Dogs , Haplorhini , Humans , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/urine , Protein Kinases/metabolism , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Pyrroles/urine , Rats , Spectrometry, Mass, Electrospray Ionization , Sulfhydryl Compounds/metabolism , Thiazolidinediones/metabolism , Triazines/chemical synthesis , Triazines/pharmacokinetics , Triazines/urine , TroglitazoneABSTRACT
A series of 3-aryl-5-acylpiperazinyl-pyrazoles (e.g., 3a-b) initially identified through a high-throughput screening campaign using the aequorin Ca(2+) bioluminescence assay as novel, potent small molecule antagonists of the G protein-coupled human tachykinin NK(3) receptor (hNK3-R) is described. Preliminary profiling revealed poor plasma and metabolic stability for these structures in rodents. Further optimization efforts resulted in analogs with improved potency, stability, and pharmacokinetic properties as well as good brain permeability, for example, compounds 26 and 42. Unexpected cytotoxicity was observed in such N-Me pyrazole structures as compounds 41-42.
Subject(s)
Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptors, Neurokinin-3/antagonists & inhibitors , Animals , Cell Line, Tumor , Drug Discovery , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Pyrazoles/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The synthesis and biological evaluation of potent and selective anaplastic lymphoma kinase (ALK) inhibitors from a novel class of 2,4-diaminopyrimidines, incorporating 2,3,4,5-tetrahydro-benzo[d]azepine fragments, is described. An orally bioavailable analogue (18) that displayed antitumor efficacy in ALCL xenograft models in mice was identified and extensively profiled.
Subject(s)
Benzazepines/chemistry , Lymphoma, Large-Cell, Anaplastic/drug therapy , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Benzazepines/pharmacokinetics , Benzazepines/therapeutic use , Mice , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/metabolism , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases , Xenograft Model Antitumor AssaysABSTRACT
Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Quinazolines/pharmacology , Urea/pharmacology , Animals , Dose-Response Relationship, Drug , Mice , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Tissue Distribution , Urea/analogs & derivatives , Urea/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine.
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists/pharmacology , Indazoles/pharmacology , Receptors, Calcitonin Gene-Related Peptide/metabolism , Spiro Compounds/pharmacology , Animals , Binding Sites , Calcitonin Gene-Related Peptide Receptor Antagonists/chemical synthesis , Calcitonin Gene-Related Peptide Receptor Antagonists/metabolism , Calcitonin Gene-Related Peptide Receptor Antagonists/toxicity , Dogs , Drug Design , Humans , Indazoles/chemical synthesis , Indazoles/metabolism , Indazoles/toxicity , Macaca fascicularis , Migraine Disorders/drug therapy , Molecular Docking Simulation , Molecular Structure , Rats , Spiro Compounds/chemical synthesis , Spiro Compounds/metabolism , Spiro Compounds/toxicity , Structure-Activity RelationshipABSTRACT
The ubiquitin-proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[(2 S,3 R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.
Subject(s)
Antineoplastic Agents/chemical synthesis , Proteasome Inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Humans , Mice , Neoplasm Transplantation , Proteasome Endopeptidase Complex/chemistry , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC Æ/Ê (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.
Subject(s)
Carcinoma, Basal Cell/drug therapy , Histone Deacetylase 1/drug effects , Histone Deacetylase Inhibitors/pharmacology , Isoenzymes/drug effects , Protein Kinase C/drug effects , Skin Neoplasms/drug therapy , Allografts , Animals , Carcinoma, Basal Cell/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Computational Biology , Drug Combinations , Drug Discovery , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Hedgehogs/genetics , Hedgehogs/metabolism , Histone Deacetylase 1/genetics , Histone Deacetylase 1/metabolism , Histone Deacetylase Inhibitors/chemistry , Isoenzymes/metabolism , Mice , Mice, Knockout , Protein Kinase C/metabolism , Signal Transduction , Transcription Factors/drug effects , Transcription Factors/genetics , Zinc Finger Protein GLI1/genetics , Zinc Finger Protein GLI1/metabolismABSTRACT
CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H3 receptor (H3R) with drug-like properties. High affinity in human (hH3R Ki = 2.0 ± 0.2 nM) and rat (rH3R Ki = 3.6 ± 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (Kb = 0.3 ± 0.1 nM) and inverse agonism (EC50 = 0.6 ± 0.2 nM) were demonstrated in [(35)S]guanosine 5(')-O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-related exposure was consistent among rat, dog, and monkey. After oral dosing, occupancy of H3R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED50 = 0.1 mg/kg p.o.). Functional antagonism in brain was demonstrated by the inhibition of R-α-methylhistamine-induced drinking in the rat dipsogenia model (ED50 = 0.92 mg/kg). CEP-32215 significantly increased wake duration in the rat EEG model at 3-30 mg/kg p.o. Increased motor activity, sleep rebound or undesirable events (such as spike wave or seizure activity) was not observed following doses up to 100 mg/kg p.o., indicating an acceptable therapeutic index. CEP-32215 may have potential utility in the treatment of a variety of sleep disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.
Subject(s)
Drug Inverse Agonism , Histamine H3 Antagonists/pharmacology , Piperidines/pharmacology , Pyrazines/pharmacology , Spiro Compounds/pharmacology , Wakefulness/drug effects , Administration, Oral , Animals , Biological Availability , Brain/drug effects , Brain/metabolism , Dogs , Drinking/drug effects , Drinking/physiology , Drug Evaluation, Preclinical , Histamine Agonists/pharmacology , Histamine H3 Antagonists/pharmacokinetics , Humans , Macaca fascicularis , Male , Methylhistamines/pharmacology , Motor Activity/drug effects , Motor Activity/physiology , Piperidines/pharmacokinetics , Pyrazines/pharmacokinetics , Rats, Sprague-Dawley , Receptors, Histamine H3/metabolism , Sleep/drug effects , Sleep/physiology , Spiro Compounds/pharmacokinetics , Wakefulness/physiologyABSTRACT
Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.