RESUMO
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.
Assuntos
Benzamidas/farmacologia , Benzocicloeptenos/farmacologia , Descoberta de Drogas , Quinase 1 de Adesão Focal/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Administração Oral , Quinase do Linfoma Anaplásico , Animais , Benzamidas/administração & dosagem , Benzamidas/química , Benzocicloeptenos/administração & dosagem , Benzocicloeptenos/química , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Quinase 1 de Adesão Focal/metabolismo , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
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'.
Assuntos
Agonismo Inverso de Drogas , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piperidinas/farmacologia , Pirazinas/farmacologia , Compostos de Espiro/farmacologia , Vigília/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cães , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Líquidos/fisiologia , Avaliação Pré-Clínica de Medicamentos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Macaca fascicularis , Masculino , Metilistaminas/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Piperidinas/farmacocinética , Pirazinas/farmacocinética , Ratos Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Sono/efeitos dos fármacos , Sono/fisiologia , Compostos de Espiro/farmacocinética , Vigília/fisiologiaRESUMO
A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6. Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1R,6S)-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H3R candidate. Diastereomer 25 had high H3R binding affinity, excellent selectivity, displayed potent H3R functional antagonism and robust wake-promoting activity in vivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development.
Assuntos
Agonismo Inverso de Drogas , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores Histamínicos H3/metabolismo , Vigília/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Desenho de Fármacos , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Piridazinas/farmacocinética , Pirrolidinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Pirróis/química , Pirróis/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Triazinas/química , Triazinas/uso terapêutico , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Linfoma Anaplásico de Células Grandes/enzimologia , Camundongos SCID , Modelos Moleculares , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/farmacocinética , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases/metabolismo , Triazinas/farmacocinéticaRESUMO
In addition to having selective potency against the molecular target(s), a compound must be able to reach its intended site of action in vivo in sufficient quantity and for the appropriate duration of time to exert a biological effect. The fate of a compound after in vivo administration depends upon its absorption, distribution, metabolism, and excretion (ADME), as well as its target residence time. The concentration of the compound in the blood, plasma, and other tissues represents the sum of all of these processes. Described in this unit are protocols for administering a compound by various routes to rats and for collecting the appropriate samples to determine the pharmacokinetics profile. The basic terms used in pharmacokinetics studies are defined, and representative examples are given to illustrate important variables to consider.
Assuntos
Farmacocinética , Anestesia por Inalação , Anestésicos Inalatórios , Animais , Coleta de Amostras Sanguíneas , Fezes/química , Feminino , Isoflurano , Masculino , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/urina , Radioisótopos/farmacocinética , Ratos/sangue , Ratos/metabolismo , Ratos/urina , Distribuição TecidualRESUMO
A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.
Assuntos
Nootrópicos/química , Piperidinas/química , Piridazinas/química , Receptores Histamínicos H3/química , Animais , Transtornos Cognitivos/tratamento farmacológico , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Meia-Vida , Haplorrinos , Memória de Curto Prazo/efeitos dos fármacos , Nootrópicos/farmacocinética , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piridazinas/farmacocinética , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Ratos , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
During SAR development of previously reported pyrrolocarbazole 1, a potent PARP-1 inhibitor, compound 14, was discovered serendipitously to be a prodrug of compound 1.
Assuntos
Carbazóis/química , Inibidores Enzimáticos/química , Ftalimidas/química , Inibidores de Poli(ADP-Ribose) Polimerases , Pró-Fármacos/química , Animais , Carbazóis/metabolismo , Carbazóis/farmacocinética , Galinhas , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Ftalimidas/metabolismo , Ftalimidas/farmacocinética , Poli(ADP-Ribose) Polimerases/metabolismo , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacocinética , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
In search of a next generation molecule to the novel wake-promoting agent modafinil, a series of aryl-heteroayl-derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually.
Assuntos
Compostos Benzidrílicos/química , Estimulantes do Sistema Nervoso Central/química , Sulfóxidos/química , Tiofenos/química , Animais , Área Sob a Curva , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/farmacocinética , Estimulantes do Sistema Nervoso Central/síntese química , Estimulantes do Sistema Nervoso Central/farmacocinética , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Meia-Vida , Modafinila , Ligação Proteica , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfóxidos/síntese química , Sulfóxidos/farmacocinética , Simportadores/química , Simportadores/metabolismo , Tiofenos/síntese química , Tiofenos/farmacocinética , Vigília/efeitos dos fármacosRESUMO
A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Agonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos H3/síntese química , Nootrópicos/síntese química , Piridazinas/síntese química , Pirrolidinas/síntese química , Receptores Histamínicos H3/química , Animais , Células CHO , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cricetinae , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Estrutura Molecular , Nootrópicos/farmacologia , Piridazinas/farmacologia , Pirrolidinas/farmacologia , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of 4-pyridazin-3-one and 5-pyridazin-3-one analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship revealed the 5-pyridazin-3-ones 8a and S-methyl 8b had excellent human and rat H(3)R affinities, and acceptable pharmacokinetic properties. In vivo evaluation of 8a showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG/EMG model.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Propilaminas/farmacologia , Piridazinas/farmacologia , Receptores Histamínicos H3/metabolismo , Animais , Antagonistas dos Receptores Histamínicos/química , Humanos , Masculino , Dados de Sequência Molecular , Estrutura Molecular , Propilaminas/síntese química , Propilaminas/química , Piridazinas/síntese química , Piridazinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Compostos Benzidrílicos/química , Fluorenos/química , Fármacos Neuroprotetores/química , Sulfóxidos/química , Animais , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fluorenos/síntese química , Fluorenos/farmacocinética , Injeções Intraperitoneais , Modafinila , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacocinética , Ratos , Sulfóxidos/síntese química , Sulfóxidos/farmacocinéticaRESUMO
Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure-activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.
Assuntos
Antineoplásicos/síntese química , Janus Quinase 2/antagonistas & inibidores , Piridinas/síntese química , Triazóis/síntese química , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Cães , Humanos , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, 25b. A striking feature of 25b over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, 25b exhibited dose proportional escalation in rat compared to compound 3 which suffered dose limiting absorption preventing further advancement. Compound 25b exhibited significant in vivo antitumor efficacy when dosed orally in an ALK-positive ALCL tumor xenograft model in SCID mice, warranting further assessment in advanced preclinical models.
Assuntos
Antineoplásicos/síntese química , Cicloeptanos/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Administração Oral , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cicloeptanos/farmacocinética , Cicloeptanos/farmacologia , Cães , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Camundongos , Camundongos SCID , Modelos Moleculares , Morfolinas/síntese química , Morfolinas/farmacocinética , Morfolinas/farmacologia , Fosforilação , Piperazinas/síntese química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases/metabolismo , Receptor de Insulina/antagonistas & inibidores , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model.
Assuntos
Agonismo Inverso de Drogas , Agonistas dos Receptores Histamínicos , Cetonas/química , Vigília/efeitos dos fármacos , 1-Propanol/química , 1-Propanol/farmacologia , Animais , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Humanos , Cetonas/farmacologia , Metilaminas/química , Metilaminas/farmacologia , Fenóis/química , Fenóis/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológicoRESUMO
A novel class of 1'-cyclobutyl-6-(4-piperidyloxy)spiro[benzopyran-2,4'-piperidine] derivatives with low nanomolar affinity for the human and rat histamine-3 receptors (H(3)Rs) are described. The spirobenzopyran piperidine ether analogs demonstrated excellent H(3)R affinity and selectivity against histamine receptor subtypes (H(1)R, H(2)R, and H(4)R), were stable in liver microsomes, and had selectivity against CYP P450 enzymes. Compounds 10, 13, 15, and 16 demonstrated high H(3)R affinity, in vitro liver microsomal stability, selectivity against CYP isoforms, moreover, these ether analogs exhibited acceptable iv pharmacokinetic (PK) properties but had poor oral exposure in rat.
Assuntos
Benzopiranos/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Piperidinas/síntese química , Receptores Histamínicos H3/metabolismo , Compostos de Espiro/síntese química , Administração Oral , Animais , Benzopiranos/farmacocinética , Benzopiranos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Antagonistas dos Receptores Histamínicos/farmacocinética , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Injeções Intravenosas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships for a series of phenoxypiperidine pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. The search for compounds with improved hERG and DAT selectivity without the formation of in vivo active metabolites identified 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one 17b. Compound 17b met discovery flow criteria, demonstrated potent H(3)R functional antagonism in vivo in the rat dipsogenia model and potent wake activity in the rat EEG/EMG model at doses as low as 0.1 mg/kg ip.
Assuntos
Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Piperidinas/química , Piridazinas/química , Receptores Histamínicos H3 , Vigília/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Modelos Moleculares , Estrutura Molecular , Piperidinas/farmacologia , Piridazinas/farmacologia , RatosRESUMO
Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.
Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Cetonas/química , Morfolinas/química , Receptores Histamínicos H3 , Vigília/efeitos dos fármacos , Animais , Eletroencefalografia , Agonistas dos Receptores Histamínicos/química , Humanos , Cetonas/farmacologia , Masculino , Estrutura Molecular , Morfolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited â¼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat social recognition test.
Assuntos
Encéfalo/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Animais , Cães , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Ratos , Receptores de Serotonina , Antagonistas da Serotonina/farmacocinética , EstereoisomerismoRESUMO
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.
Assuntos
Cognição/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/farmacologia , Nootrópicos , Piridazinas/farmacologia , Pirrolidinas/farmacologia , Vigília/efeitos dos fármacos , Animais , Autorradiografia , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , DNA Complementar/biossíntese , DNA Complementar/genética , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Sono/efeitos dos fármacos , Comportamento SocialRESUMO
Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.