RESUMO
A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead.
Assuntos
Analgésicos/uso terapêutico , Benzamidas/uso terapêutico , Dor/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Piridinas/uso terapêutico , Receptores Purinérgicos P2X3/metabolismo , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacocinética , Animais , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacocinética , Cães , Desenho de Fármacos , Interações Medicamentosas , Glucuronosiltransferase/antagonistas & inibidores , Meia-Vida , Hiperbilirrubinemia/prevenção & controle , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound 27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound 27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency.
Assuntos
Imidazóis/química , Piridinas/química , Piridonas/química , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Imidazóis/sangue , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Locomoção/efeitos dos fármacos , Ligação Proteica , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/patologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Piridonas/sangue , Piridonas/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldo-ketoreductases, was a reversible time-dependent inhibitor (k(inact) = 0.12 minute(-1), K(I) = 6.1 µM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC(50) of 18 and 4.9 µM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions.
Assuntos
Antivirais/metabolismo , Inibidores Enzimáticos/metabolismo , Enzimas/metabolismo , Fígado/enzimologia , Moduladores de Transporte de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Prolina/análogos & derivados , Animais , Antivirais/toxicidade , Biotransformação , Células CHO , Cricetinae , Cricetulus , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Cães , Relação Dose-Resposta a Droga , Interações Medicamentosas , Inibidores Enzimáticos/toxicidade , Enzimas/genética , Feminino , Glucuronosiltransferase/metabolismo , Humanos , Cinética , Células LLC-PK1 , Fígado/efeitos dos fármacos , Transportador 1 de Ânion Orgânico Específico do Fígado , Células Madin Darby de Rim Canino , Masculino , Moduladores de Transporte de Membrana/toxicidade , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Microssomos Hepáticos/enzimologia , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Oxirredutases/metabolismo , Prolina/metabolismo , Prolina/toxicidade , Proteínas Recombinantes/metabolismo , Suínos , TransfecçãoRESUMO
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
Assuntos
Ácidos Nicotínicos/química , Ácidos Nicotínicos/farmacologia , Antagonistas dos Receptores de Orexina , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Receptores de Orexina/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
SETD2, a lysine N-methyltransferase, is a histone methyltransferase that plays an important role in various cellular processes and was identified as a target of interest in multiple myeloma that features a t(4,14) translocation. We recently reported the discovery of a novel small-molecule SETD2 inhibitor tool compound that is suitable for preclinical studies. Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation. Further optimization of this chemical series led to the discovery of EZM0414, which is a potent, selective, and orally bioavailable inhibitor of SETD2 with good pharmacokinetic properties and robust pharmacodynamic activity in a mouse xenograft model.
RESUMO
PURPOSE: To systemically investigate, for a therapeutic protein with a circulating soluble target, how the interplay of target dynamics and drug pharmacokinetics defines the 'total' and 'free' drug and target temporal profiles. METHOD: By extending the established rapid-binding target-mediated drug disposition (TMDD) pharmacokinetic model to circulating soluble targets, the temporal profiles of 'total' and 'free' drug and target were simulated with varying binding affinity (K(D)), target baseline (R(ss)), target turnover, and drug dose level. Two sets of published experimental data were compared with the simulated results. RESULTS: Binding to a circulating soluble target could lead to a divergence of the 'free' drug from the 'total' drug. Simulations show this divergent magnitude determined by K(D) and R(ss), with the temporal profile being defined by target turnover and drug dose level. As divergence proceeds, starting at the distribution phase, 'free' drug would decline faster but eventually parallel 'total' drug at the terminal phase, giving rise to a steeper distribution phase and comparable terminal half-life, relative to the 'total' form. The model also allows for estimation of the dynamic change of 'total' and 'free' target in response to the treatment of a therapeutic protein drug, facilitating dose level and regimen design to achieve desired 'free' target suppression. Model predictions compared favorably with two sets of published experimental data. CONCLUSIONS: Theoretical analyses identified key variables governing the different temporal profiles of 'total' and 'free' drug and target. The rapid-binding TMDD model reasonably captured the features of the interplay of drug pharmacokinetics and target dynamics for two reported cases.
Assuntos
Modelos Biológicos , Proteínas/farmacologia , Proteínas/farmacocinética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/farmacologia , Simulação por Computador , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Imunoglobulina G/metabolismo , Inativação Metabólica , Camundongos , Camundongos SCID , Ligação Proteica , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep.
Assuntos
Amidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Animais , Camundongos , Ratos , Ratos WistarRESUMO
The recent approval of aducanumab for Alzheimer's disease has heightened the interest in therapies targeting the amyloid hypothesis. Our research has focused on identification of novel compounds to improve amyloid processing by modulating gamma secretase activity, thereby addressing a significant biological deficit known to plague the familial form of the disease. Herein, we describe the design, synthesis, and optimization of new gamma secretase modulators (GSMs) based on previously reported oxadiazine 1. Potency improvements with a focus on predicted and measured properties afforded high-quality compounds further differentiated via robust Aß42 reductions in both rodents and nonhuman primates. Extensive preclinical profiling, efficacy studies, and safety studies resulted in the nomination of FRM-024, (+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-(6-methoxy-5-(4-methyl-1H-imidazole-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine, as a GSM preclinical candidate for familial Alzheimer's disease.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Encéfalo/metabolismo , Descoberta de Drogas , Inibidores e Moduladores de Secretases gama/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Área Sob a Curva , Cães , Inibidores e Moduladores de Secretases gama/farmacocinética , Meia-Vida , Haplorrinos , Humanos , Camundongos , Fragmentos de Peptídeos/metabolismo , RatosRESUMO
SET domain-containing protein 2 (SETD2), a histone methyltransferase, has been identified as a target of interest in certain hematological malignancies, including multiple myeloma. This account details the discovery of EPZ-719, a novel and potent SETD2 inhibitor with a high selectivity over other histone methyltransferases. A screening campaign of the Epizyme proprietary histone methyltransferase-biased library identified potential leads based on a 2-amidoindole core. Structure-based drug design (SBDD) and drug metabolism/pharmacokinetics (DMPK) optimization resulted in EPZ-719, an attractive tool compound for the interrogation of SETD2 biology that enables in vivo target validation studies.
RESUMO
Animal models are used commonly in various stages of drug discovery and development to aid in the prospective assessment of drug-drug interaction (DDI) potential and the understanding of the underlying mechanism for DDI of a drug candidate. In vivo assessments in an appropriate animal model can be very valuable, when used in combination with in vitro systems, to help verify in vivo relevance of the in vitro animal-based results, and thus substantiate the extrapolation of in vitro human data to clinical outcomes. From a pharmacokinetic standpoint, a key consideration for rational selection of an animal model is based on broad similarities to humans in important physiological and biochemical parameters governing drug absorption, distribution, metabolism or excretion (ADME) processes in question for both the perpetrator and victim drugs. Equally critical are specific in vitro and/or in vivo experiments to demonstrate those similarities, usually both qualitative and quantitative, in the ADME properties/processes under investigation. In this review, theoretical basis and specific examples are presented to illustrate the utility of the animal models in assessing the potential and understanding the mechanisms of DDIs.
Assuntos
Descoberta de Drogas/métodos , Interações Medicamentosas , Drogas em Investigação/farmacocinética , Modelos Animais , Animais , Humanos , Especificidade da EspécieRESUMO
A new class of indazole-derived bradykinin B(1) antagonists and their structure-activity relationships (SAR) is reported. A number of compounds were found to have low-nanomolar affinity for the human B(1) receptor and possess acceptable P-gp and pharmacokinetics properties.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Indazóis/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Humanos , Indazóis/farmacocinética , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.
Assuntos
Alcanos/farmacologia , Descoberta de Drogas , Hipnóticos e Sedativos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Alcanos/química , Alcanos/farmacocinética , Animais , Compostos Aza/química , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Disponibilidade Biológica , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacocinética , Compostos Bicíclicos com Pontes/farmacologia , Eletroencefalografia , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacocinética , Receptores de Orexina , Ratos , Ratos Sprague-DawleyRESUMO
The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca(2+) channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Quinazolinonas/química , Quinazolinonas/farmacologia , Animais , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Cromatografia Líquida de Alta Pressão , Descoberta de Drogas , Haplorrinos , Humanos , Quinazolinonas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Hit to lead optimization of (5R)-5-hexyl-3-phenyl-1,3-oxazolidin-2-one as a positive allosteric modulator of mGluR2 is described. Improvements in potency and metabolic stability were achieved through SAR on both ends of the oxazolidinone. An optimized lead compound was found to be brain penetrant and active in a rat ketamine-induced hyperlocomotion model for antipsychotic activity.
Assuntos
Oxazolidinonas/química , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamento farmacológico , Regulação Alostérica , Animais , Antipsicóticos , Ketamina/toxicidade , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/agonistas , Relação Estrutura-AtividadeRESUMO
Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Cães , Descoberta de Drogas , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacocinética , Humanos , Macaca mulatta , Masculino , Células PC12 , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tauopatias/tratamento farmacológico , beta-N-Acetil-Hexosaminidases/química , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
After oral treatment (once daily) for 4 weeks with the potent bradykinin B(1) receptor antagonist methyl 3-chloro-3'-fluoro-4'-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)-amino]ethyl}-1,1'-biphenyl-2-carboxylate (MK-0686), rhesus monkeys (Macaca mulatta) exhibited significantly reduced systemic exposure of the compound in a dose-dependent manner, suggesting an occurrence of autoinduction of MK-0686 metabolism. This possibility is supported by two observations. 1) MK-0686 was primarily eliminated via biotransformation in rhesus monkeys, with oxidation on the chlorophenyl ring as one of the major metabolic pathways. This reaction led to appreciable formation of a dihydrodiol (M11) and a hydroxyl (M13) product in rhesus liver microsomes supplemented with NADPH. 2) The formation rate of these two metabolites determined in liver microsomes from MK-0686-treated groups was > or = 2-fold greater than the value for a control group. Studies with recombinant rhesus P450s and monoclonal antibodies against human P450 enzymes suggested that CYP2C75 played an important role in the formation of M11 and M13. The induction of this enzyme by MK-0686 was further confirmed by a concentration-dependent increase of its mRNA in rhesus hepatocytes, and, more convincingly, the enhanced CYP2C proteins and catalytic activities toward CYP2C75 probe substrates in liver microsomes from MK-0686-treated animals. Furthermore, a good correlation was observed between the rates of M11 and M13 formation and hydroxylase activities toward probe substrates determined in a panel of liver microsomal preparations from control and MK-0686-treated animals. Therefore, MK-0686, both a substrate and inducer for CYP2C75, caused autoinduction of its own metabolism in rhesus monkeys by increasing the expression of this enzyme.
Assuntos
Acetamidas/farmacocinética , Benzoatos/farmacocinética , Antagonistas de Receptor B1 da Bradicinina , Sistema Enzimático do Citocromo P-450/metabolismo , Acetamidas/sangue , Acetamidas/urina , Animais , Benzoatos/sangue , Benzoatos/urina , Bile/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Sistema Enzimático do Citocromo P-450/genética , Feminino , Hepatócitos/metabolismo , Humanos , Macaca mulatta , Masculino , Microssomos Hepáticos/metabolismo , Receptor de Pregnano X , Receptor B1 da Bradicinina/metabolismo , Receptores de Esteroides/metabolismo , Proteínas Recombinantes/metabolismoRESUMO
The design and synthesis of a novel class of human bradykinin B1 antagonists featuring difluoroethyl ether and isoxazole carboxamide moieties are disclosed. Compound 7g displayed excellent pharmacokinetic properties, efficient ex vivo receptor occupancy, and low potential for P450 induction via PXR activation.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Isoxazóis/farmacologia , Receptores de Esteroides/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Isoxazóis/farmacocinética , Macaca mulatta , Receptor de Pregnano X , Ratos , Ratos Sprague-DawleyRESUMO
A series of carbo- and heterocyclic alpha-hydroxy amide-derived bradykinin B1 antagonists was prepared and evaluated. A 4,4-difluorocyclohexyl alpha-hydroxy amide was incorporated along with a 2-methyl tetrazole in lieu of an oxadiazole to afford a suitable compound with good pharmacokinetic properties, CNS penetration, and clearance by multiple metabolic pathways.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Tetrazóis/síntese química , Tetrazóis/farmacologia , Amidas/química , Amidas/farmacocinética , Animais , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Assuntos
Amidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Amidas/química , Amidas/farmacocinética , Animais , Disponibilidade Biológica , Barreira Hematoencefálica , Inibidores das Enzimas do Citocromo P-450 , Cães , Meia-Vida , Humanos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A key challenge in the development of precision medicine is defining the phenotypic consequences of pharmacological modulation of specific target macromolecules. To address this issue, a variety of genetic, molecular and chemical tools can be used. All of these approaches can produce misleading results if the specificity of the tools is not well understood and the proper controls are not performed. In this paper we illustrate these general themes by providing detailed studies of small molecule inhibitors of the enzymatic activity of two members of the SMYD branch of the protein lysine methyltransferases, SMYD2 and SMYD3. We show that tool compounds as well as CRISPR/Cas9 fail to reproduce many of the cell proliferation findings associated with SMYD2 and SMYD3 inhibition previously obtained with RNAi based approaches and with early stage chemical probes.