RESUMO
The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates (n = 96) with a MIC range of 0.016 to 0.25 µg/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 µg/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 µg/ml), especially Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 µg/ml) which indicated that it was 8-fold more potent than voriconazole. In vivo, once-daily intranasal administration of PC1244 (3.2 to 80 µg/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showed in vivo effects superior to those of 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans.
Assuntos
Antifúngicos/farmacologia , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/efeitos dos fármacos , Azóis/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Proteínas Fúngicas/genética , Triazóis/farmacologia , Administração Intranasal , Animais , Aspergillus fumigatus/isolamento & purificação , Candida/efeitos dos fármacos , Cryptococcus/efeitos dos fármacos , Citocinas/sangue , Farmacorresistência Fúngica , Células Epiteliais/metabolismo , Ergosterol/biossíntese , Proteínas Fúngicas/antagonistas & inibidores , Galactose/análogos & derivados , Humanos , Hifas/metabolismo , Mananas/sangue , Camundongos , Testes de Sensibilidade Microbiana , Rhizopus/efeitos dos fármacos , Trichophyton/efeitos dos fármacos , Voriconazol/farmacologiaRESUMO
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
Assuntos
Anti-Inflamatórios/química , Isoindóis/química , Receptores de Prostaglandina E Subtipo EP4/agonistas , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Células Sanguíneas/citologia , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Dinoprostona/química , Dinoprostona/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Concentração Inibidora 50 , Isoindóis/farmacocinética , Isoindóis/uso terapêutico , Lipopolissacarídeos/farmacologia , Dor/tratamento farmacológico , Dor/patologia , Dor/veterinária , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Acute myeloid leukaemia (AML) is an aggressive type of leukaemia with low rates of long-term survival. While the current standard of care is based on cytotoxic chemotherapy, a promising emerging approach is differentiation therapy. However, most current differentiating agents target specific mutations and are effective only in certain patient subtypes. To identify agents which may be effective in wider population cohorts, we performed a phenotypic screen with the myeloid marker CD11b and identified a compound series that was able to differentiate AML cell lines in vitro regardless of their mutation status. Structure-activity relationship studies revealed that replacing the formamide and catechol methyl ether groups with sulfonamide and indazole respectively improved the in vitro metabolic profile of the series while maintaining the differentiation profile in multiple cell lines. This optimisation exercise enabled progression of a lead compound to in vivo efficacy testing. Our work supports the promise of phenotypic screening to identify novel small molecules that induce differentiation in a wide range of AML subtypes.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular , Diferenciação Celular , Piridinas/farmacologiaRESUMO
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.
Assuntos
Anti-Inflamatórios não Esteroides/química , Benzofuranos/química , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/uso terapêutico , Benzofuranos/farmacocinética , Benzofuranos/uso terapêutico , Linhagem Celular , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Dor/tratamento farmacológico , Ratos , Receptores de Prostaglandina E Subtipo EP1/metabolismo , Relação Estrutura-AtividadeRESUMO
This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.
Assuntos
Acetatos/química , Secretases da Proteína Precursora do Amiloide/fisiologia , Piperidinas/química , Acetatos/metabolismo , Acetatos/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular Tumoral , Cães , Humanos , Camundongos , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/metabolismo , Piperidinas/metabolismo , Piperidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato/efeitos dos fármacosRESUMO
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Arginina/química , Etilaminas/química , Inibidores de Proteases/química , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Etilaminas/síntese química , Etilaminas/uso terapêutico , Inibidores de Proteases/síntese química , Inibidores de Proteases/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
Assuntos
Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Piridinas/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Piridinas/química , Piridinas/uso terapêutico , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
We describe the medicinal chemistry programme that led to the identification of the EP(1) receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP(1) antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
Assuntos
Analgésicos/síntese química , Química Farmacêutica/métodos , Inflamação/tratamento farmacológico , Ácidos Nicotínicos/síntese química , Piridinas/síntese química , Receptores de Prostaglandina E/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , Desenho de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Modelos Químicos , Ácidos Nicotínicos/farmacologia , Piridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etilaminas/química , Inibidores de Proteases/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Disponibilidade Biológica , Cães , Etilaminas/síntese química , Etilaminas/farmacocinética , Camundongos , Camundongos Knockout , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB(2) receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.
Assuntos
Analgésicos/síntese química , Piridinas/síntese química , Piridinas/uso terapêutico , Receptor CB2 de Canabinoide/agonistas , Amidas/síntese química , Amidas/farmacologia , Amidas/uso terapêutico , Analgesia/métodos , Animais , Modelos Animais de Doenças , Descoberta de Drogas/métodos , Inflamação , Dor/tratamento farmacológico , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etilaminas/química , Inibidores de Proteases/química , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Etilaminas/síntese química , Etilaminas/farmacologia , Humanos , Camundongos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologiaRESUMO
Many years of work have been invested in the identification of potent and selective COX-2 inhibitors for the treatment of chronic inflammatory pain. One issue faced by workers is the balance between the lipophilicity required for potent enzyme inhibition and the physical properties necessary for drug absorption and distribution in vivo. Frequently approaches to reduce lipophilicity through introduction of polar functionality is hampered by highly challenging chemistry to prepare key molecules. We have complemented traditional synthetic chemistry with a biotransformations approach which efficiently provided access to an array of key target molecules.
Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Biotransformação , Química Farmacêutica/métodos , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Humanos , Inflamação/tratamento farmacológico , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Tiazinas/química , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Simulação por Computador , Etilaminas/síntese química , Etilaminas/química , Etilaminas/farmacologia , Humanos , Camundongos , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/farmacocinéticaRESUMO
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
Assuntos
Aminas/síntese química , Inibidores de Ciclo-Oxigenase 2/síntese química , Éteres/síntese química , Pirimidinas/síntese química , Sulfonas/síntese química , Aminas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Farmacêutica/métodos , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Éteres/farmacologia , Humanos , Inflamação , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Pirimidinas/farmacologia , Ratos , Sulfonas/farmacologiaRESUMO
BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzotiadiazinas/síntese química , Óxidos S-Cíclicos/síntese química , Etilaminas/síntese química , Administração Oral , Animais , Benzotiadiazinas/farmacocinética , Benzotiadiazinas/farmacologia , Disponibilidade Biológica , Óxidos S-Cíclicos/farmacocinética , Óxidos S-Cíclicos/farmacologia , Cães , Etilaminas/farmacocinética , Etilaminas/farmacologia , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
The possible neuroprotective role of a novel and highly selective cyclooxygenase-2 inhibitor GW637185X was studied in a model of acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced injury of nigrostriatal dopaminergic (DA) neurons in the mouse. Stereological and microdensitometrical analysis of nigral tyrosine hydroxylase-immunoreactive cell bodies and striatal tyrosine hydroxylase-immunoreactive terminals, respectively, showed that GW637185X exerted a full protection against MPTP-induced degeneration of the nigro-striatal pathway. In contrast to earlier studies, these findings demonstrate that acute inhibition of cyclooxygenase-2 can result in a full neuroprotective effect not only on nigral DA cell bodies, but also on striatal DA terminals in the mouse MPTP model.
Assuntos
Encéfalo/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Intoxicação por MPTP/tratamento farmacológico , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Dopamina/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/induzido quimicamente , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
We describe the medicinal chemistry approach that generated a novel indole series of EP(1) receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain.
Assuntos
Indóis/síntese química , Indóis/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/metabolismo , Animais , Humanos , Ligação de Hidrogênio , Indóis/química , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
We describe the SAR, in terms of heterocyclic replacements, for a series of pyrazole EP(1) receptor antagonists. This study led to the identification of several aromatic heterocyclic replacements for the pyrazole in the original compound. Investigation of replacements for the methylene linker uncovered disparate SAR in the thiazole and pyridine series.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Analgésicos/química , Animais , Encéfalo/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Química Combinatória , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estrutura Molecular , Medição da Dor , Pirazóis/química , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
We describe the discovery of a series of pyrazole amide EP(1) receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1-2.0:1 in addition to good solubility and metabolic stability.