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1.
Bioorg Med Chem Lett ; 25(7): 1621-6, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25708617

RESUMO

Early lead compounds in this gamma secretase modulator series were found to potently inhibit CYP3A4 and other human CYP isoforms increasing their risk of causing drug-drug-interactions (DDIs). Using structure-activity relationships and CYP3A4 structural information, analogs were developed that minimized this DDI potential. Three of these new analogs were further characterized by rat PK, rat PK/PD and rat exploratory toxicity studies resulting in selection of SPI-1865 (14) as a preclinical development candidate.


Assuntos
Azetidinas/farmacologia , Produtos Biológicos/farmacologia , Citocromo P-450 CYP3A/metabolismo , Esteroides/farmacologia , Animais , Azetidinas/química , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Esteroides/química , Relação Estrutura-Atividade
2.
Alzheimers Res Ther ; 5(2): 19, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23597079

RESUMO

INTRODUCTION: Modulation of the gamma-secretase enzyme, which reduces the production of the amyloidogenic Aß42 peptide while sparing the production of other Aß species, is a promising therapeutic approach for the treatment of Alzheimer's disease. Satori has identified a unique class of small molecule gamma-secretase modulators (GSMs) capable of decreasing Aß42 levels in cellular and rodent model systems. The compound class exhibits potency in the nM range in vitro and is selective for lowering Aß42 and Aß38 while sparing Aß40 and total Aß levels. In vivo, a compound from the series, SPI-1865, demonstrates similar pharmacology in wild-type CD1 mice, Tg2576 mice and Sprague Dawley rats. METHODS: Animals were orally administered either a single dose of SPI-1865 or dosed for multiple days. Aß levels were measured using a sensitive plate-based ELISA system (MSD) and brain and plasma exposure of drug were assessed by LC/MS/MS. RESULTS: In wild-type mice using either dosing regimen, brain Aß42 and Aß38 levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aß40 was observed, reflecting the changes observed in vitro. In rats, brain Aß levels were examined and similar to the mouse studies, brain Aß42 and Aß38 were lowered. Comparable changes were also observed in the Tg2576 mice, where Aß levels were measured in brain as well as plasma and CSF. CONCLUSIONS: Taken together, these data indicate that SPI-1865 is orally bioavailable, brain penetrant, and effective at lowering Aß42 in a dose responsive manner. With this unique profile, the class of compounds represented by SPI-1865 may be a promising new therapy for Alzheimer's disease.

3.
J Med Chem ; 55(21): 9270-82, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-23030762

RESUMO

A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compounds with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochemical properties of the analogues. This strategy gave compounds with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compounds, 100 and 120, were tested for a pharmacodynamic effect in the strain and lowered brain Aß42 levels.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Produtos Biológicos/química , Triterpenos/química , Administração Oral , Peptídeos beta-Amiloides/metabolismo , Animais , Disponibilidade Biológica , Produtos Biológicos/farmacocinética , Produtos Biológicos/farmacologia , Barreira Hematoencefálica/metabolismo , Carbamatos/química , Carbamatos/farmacocinética , Carbamatos/farmacologia , Éteres/química , Éteres/farmacocinética , Éteres/farmacologia , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Fragmentos de Peptídeos/metabolismo , Permeabilidade , Ratos , Relação Estrutura-Atividade , Triterpenos/farmacocinética , Triterpenos/farmacologia
4.
Int J Alzheimers Dis ; 2012: 210756, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23320246

RESUMO

The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)-formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline-are triggered by Aß peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since γ-secretase is critical for Aß production, many in the biopharmaceutical community focused on γ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control γ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aß peptides without affecting other γ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of γ-secretase activity have been discovered that spare the ε cleavage of APP and other substrates while decreasing the production of Aß(42). Multiple chemical classes of γ-secretase modulators have been identified which differ in the pattern of Aß peptides produced. Ideally, modulators will allow the ε cleavage of all substrates while shifting APP cleavage from Aß(42) and other highly amyloidogenic Aß peptides to shorter and less neurotoxic forms of the peptides without altering the total Aß pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity.

5.
ACS Med Chem Lett ; 3(11): 908-13, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900406

RESUMO

The discovery of a new series of γ-secretase modulators is disclosed. Starting from a triterpene glycoside γ-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compounds with significantly improved central nervous system (CNS) exposure.

6.
Bioorg Med Chem Lett ; 21(9): 2631-6, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21269825

RESUMO

The synthesis and structure-activity relationship (SAR) of a novel series of di-substituted imidazoles, derived from modification of DAPT, are described. Subsequent optimization led to identification of a highly potent series of inhibitors that contain a ß-amine in the imidazole side-chain resulting in a robust in vivo reduction of plasma and brain Aß in guinea pigs. The therapeutic index between Aß reductions and changes in B-cell populations were studied for compound 10 h.


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Aminação/efeitos dos fármacos , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/metabolismo , Animais , Bioensaio , Diamida/síntese química , Diamida/química , Diamida/farmacologia , Inibidores Enzimáticos/química , Cobaias , Células HeLa , Humanos , Imidazóis/química , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 21(9): 2637-40, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21269827

RESUMO

A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aß in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aß EC(50) lead to the identification of compound 14f (PF-3084014) which was selected for clinical development.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/farmacologia , Valina/análogos & derivados , Animais , Bioensaio , Desenho de Fármacos , Inibidores Enzimáticos/química , Cobaias , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/química , Valina/síntese química , Valina/química , Valina/farmacologia
8.
J Med Chem ; 53(3): 1222-37, 2010 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-20043678

RESUMO

A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.


Assuntos
Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacologia , Nootrópicos/síntese química , Nootrópicos/farmacologia , Oxazóis/síntese química , Oxazóis/farmacologia , Receptores Nicotínicos/química , Esquizofrenia/tratamento farmacológico , Animais , Compostos Azabicíclicos/química , Disponibilidade Biológica , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Agonistas Nicotínicos/química , Nootrópicos/química , Oócitos/efeitos dos fármacos , Oxazóis/química , Ratos , Pele/citologia , Pele/efeitos dos fármacos , Relação Estrutura-Atividade , Xenopus laevis/crescimento & desenvolvimento , Receptor Nicotínico de Acetilcolina alfa7
9.
Bioorg Med Chem Lett ; 19(11): 2974-6, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19410451

RESUMO

The type 1 glycine transporter plays an important in regulating homeostatic glycine levels in the brain that are relevant to the activation of the NMDA receptor by the excitatory neurotransmitter glutamate. We describe herein the structure-activity relationships (SAR) of a structurally novel class of GlyT1 inhibitors following on a lead derived from high throughput screening, which shows good selectivity for GlyT1 and potent activity in elevating CSF levels of glycine.


Assuntos
Compostos Aza/química , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Compostos Heterocíclicos com 2 Anéis/química , Compostos Aza/síntese química , Compostos Aza/farmacologia , Linhagem Celular , Desenho de Fármacos , Glicina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 17(7): 1996-9, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17276061

RESUMO

The synthesis of a novel gut selective MTP inhibitor, 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), and its in vitro and in vivo profile are described. Dirlotapide (3) demonstrated excellent potency against MTP enzyme in HepG2 cells and canine hepatocytes. This novel MTP inhibitor also showed excellent efficacy when tested in a canine food intake model.


Assuntos
Carbamatos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntese química , Proteínas de Transporte/antagonistas & inibidores , Química Farmacêutica/métodos , Indóis/síntese química , Obesidade/tratamento farmacológico , Animais , Carbamatos/química , Carbamatos/farmacologia , Ácidos Carboxílicos/farmacologia , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Ratos
12.
Bioorg Med Chem ; 13(5): 1805-9, 2005 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15698798

RESUMO

The synthesis of a novel canine COX-2 selective inhibitor, 2-(3-difluoromethyl-5-phenylpyrazol-1-yl)-5-methanesulfonylpyridine, and its in vitro and in vivo profile are described. Pyrazole 8 demonstrated excellent potency and selectivity for canine COX-2 in both in vitro and ex vivo whole blood assays. This novel COX-2 inhibitor also showed a good pharmacokinetic profile (pk) following oral (po), intravenous (iv), and subcutaneous (sc) dosing and demonstrated excellent in vivo efficacy in a canine synovitis model.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Animais , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Cães , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Pirazóis/síntese química , Piridinas/síntese química
13.
J Antibiot (Tokyo) ; 57(4): 280-8, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15217193

RESUMO

Several novel 15-membered-ring macrolide agents (azalide 1, triamilides 2 and 3, and the azalide 3,6-ketal 4) were identified as potential antibacterial agents against Mannheimia (formerly named as Pasteurella) haemolytica, Pasteurella multocida, Haemophilus somnus and Actinobacillus pleuropneumoniae, important etiological agents of bovine and porcine respiratory disease. Compound 3 is the major component of the antibiotic tulathromycin. Antibacterial activity against tilmicosin-resistant P. multocida field isolates was also tested. In vitro MIC 50/90 analysis revealed that the four newly synthesized compounds were more potent than tilmicosin against M. haemolytica (4 to approximately 8x), P. multocida (8 to approximately 16x), A. pleuropneumoniae (4x), H. somnus (2x and 16x), and tilmicosin-resistant P. multocida (32x). In time-kill kinetic studies, all four novel compounds and tilmicosin showed bactericidal activity against M. haemolytica, P. multocida and A. pleuropneumoniae at both 4x and 8x MIC. A functional assay using genetically defined mutants revealed that all four novel compounds were poorer substrates for the efflux pump, AcrA/B system, than tilmicosin. A pH study using LPS mutants indicated that the enhanced in vitro potency of the triamilides, particularly compound 3 was mainly due to better penetration of the molecule through the outer membrane. The third amine group at the C-4'' position of the triamilde molecules contributed to this increased membrane penetration by increasing overall basicity. These studies indicate that the four novel compounds have potential as antibacterial agents against bovine and porcine respiratory disease.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Macrolídeos/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Animais , Bovinos , Doenças dos Bovinos/microbiologia , Cinética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Suínos , Doenças dos Suínos/microbiologia
14.
Bioorg Med Chem Lett ; 14(1): 95-8, 2004 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-14684306

RESUMO

Structure-activity relationship (SAR) studies of 2-[3-di(and tri)fluoromethyl-5-arylpyrazol-1-yl]-5-methanesulfonylpyridine derivatives for canine COX enzymes are described. This led to the identification of 12a as a lead candidate for further progression. The in vitro and in vivo activity of 12a for the canine COX-2 enzyme as well as its in vivo efficacy and pharmacokinetic properties in dog are highlighted.


Assuntos
Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/química , Isoenzimas/antagonistas & inibidores , Piridinas/administração & dosagem , Piridinas/química , Administração Oral , Animais , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Cães , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 12(19): 2771-4, 2002 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-12217373

RESUMO

The stereoselective synthesis of two novel series of tribasic macrocyclic antibiotics with potent in vitro activity against Pasteurella multocida and Escherichia coli strains of bacteria is described. The in vitro activity can be significantly influenced by the nature of the substituents on the C-4" aminoalcohol, with the stereochemistry of the C-4" alcohol playing a less critical role. The effect of substitution and stereochemistry on the in vivo activity in a murine model of respiratory infection is also described.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Animais , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Infecções Bacterianas/virologia , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Indicadores e Reagentes , Macrolídeos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Infecções por Pasteurella/tratamento farmacológico , Infecções por Pasteurella/microbiologia , Pasteurella multocida/efeitos dos fármacos , Estereoisomerismo
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