RESUMO
Substantial evidence implicates ß-amyloid (Aß) peptides in the etiology of Alzheimer's disease (AD). Aß is produced by the proteolytic cleavage of the amyloid precursor protein by ß- and γ-secretase suggesting that γ-secretase inhibition may provide therapeutic benefit for AD. Although many γ-secretase inhibitors have been shown to be potent at lowering Aß, some have also been shown to have side effects following repeated administration. All of these side effects can be attributed to altered Notch signaling, another γ-secretase substrate. Here we describe the in vivo characterization of the novel γ-secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering Aß, Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of Aß. However, additional studies revealed that both partial but sustained lowering of Aßand complete but less sustained lowering of Aß were successful approaches for managing Notch-related side effects. Further, changes in several Notch-related biomarkers paralleled the side effect observations. Taken together, these studies demonstrated that, by carefully varying the extent and duration of Aß lowering by γ-secretase inhibitors, it is possible to obtain robust and sustained lowering of Aß without evidence of Notch-related side effects.
RESUMO
An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzopiranos/síntese química , Benzopiranos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Sulfonas/síntese química , Sulfonas/farmacologia , Benzopiranos/química , Ciclização , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piranos/síntese química , Piranos/química , Piranos/farmacologia , Relação Estrutura-Atividade , Sulfonas/químicaRESUMO
Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aß(42) in various animal models.
Assuntos
Amidinas/síntese química , Secretases da Proteína Precursora do Amiloide/metabolismo , Oxidiazóis/síntese química , Oxazinas/síntese química , Amidinas/farmacocinética , Amidinas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Cães , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Oxazinas/farmacocinética , Oxazinas/farmacologia , Fragmentos de Peptídeos/metabolismo , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Accumulation of the ß-amyloid (Aß) peptides is one of the major pathologic hallmarks in the brains of Alzheimer's disease (AD) patients. Aß is generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) catalyzed by ß- and γ-secretases. Inhibition of Aß production by γ-secretase inhibitors (GSIs) is thus being pursued as a target for treatment of AD. In addition to processing APP, γ-secretase also catalyzes proteolytic cleavage of other transmembrane substrates, with the best characterized one being the cell surface receptor Notch. GSIs reduce Aß production in animals and humans but also cause significant side effects because of the inhibition of Notch processing. The development of GSIs that reduce Aß production and have less Notch-mediated side effect liability is therefore an important goal. γ-Secretase is a large membrane protein complex with four components, two of which have multiple isoforms: presenilin (PS1 or PS2), aph-1 (aph-1a or aph-1b), nicastrin, and pen-2. Here we describe the reconstitution of four γ-secretase complexes in Sf9 cells containing PS1--aph-1a, PS1--aph-1b, PS2--aph-1a, and PS2--aph-1b complexes. While PS1--aph-1a, PS1--aph-1b, and PS2--aph-1a complexes displayed robust γ-secretase activity, the reconstituted PS2--aph-1b complex was devoid of detectable γ-secretase activity. γ-Secretase complexes containing PS1 produced a higher proportion of the toxic species Aß42 than γ-secretase complexes containing PS2. Using the reconstitution system, we identified MRK-560 and SCH 1500022 as highly selective inhibitors of PS1 γ-secretase activity. These findings may provide important insights into developing a new generation of γ-secretase inhibitors with improved side effect profiles.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Óxidos S-Cíclicos/química , Inibidores Enzimáticos/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Presenilina-1/química , Presenilina-2/química , Sulfonamidas/química , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Células Cultivadas , Óxidos S-Cíclicos/metabolismo , Inibidores Enzimáticos/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Presenilina-1/metabolismo , Presenilina-2/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Sulfonamidas/metabolismoRESUMO
Complex tetracyclic sulfones were designed as gamma-secretase inhibitors and a stereoselective synthesis was achieved. Gamma-secretase activity was seen predominately in the (-) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/síntese química , Sulfonas/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Desenho de Fármacos , Hepatócitos/metabolismo , Humanos , Camundongos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologiaRESUMO
Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Citocromo P-450 CYP3A/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/química , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Piperidinas/síntese química , Piperidinas/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Administração Oral , Peptídeos beta-Amiloides/biossíntese , Animais , Área Sob a Curva , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Espectroscopia de Ressonância Magnética , Camundongos , Conformação Molecular , Peso Molecular , Oxirredutases/metabolismoRESUMO
Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Área Sob a Curva , Cristalografia por Raios X , Inibidores Enzimáticos/farmacocinética , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Conformação Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Piperidinas/química , Inibidores de Proteases/química , Concentração Inibidora 50 , Piperidinas/síntese química , Inibidores de Proteases/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The development of a novel series of tetrahydroquinoline-derived gamma-secretase inhibitors for the potential treatment of Alzheimer's disease is described.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/química , Quinolinas/química , Sulfonamidas/química , Humanos , Inibidores de Proteases/síntese química , Quinolinas/síntese química , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.
Assuntos
Alcaloides/síntese química , Fibrinolíticos/síntese química , Furanos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Naftalenos/síntese química , Piperidinas/síntese química , Piridinas/síntese química , Receptor PAR-1/antagonistas & inibidores , Administração Oral , Alcaloides/química , Alcaloides/farmacologia , Animais , Disponibilidade Biológica , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Cromatografia Líquida de Alta Pressão , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Furanos/química , Furanos/farmacologia , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Técnicas In Vitro , Macaca fascicularis , Naftalenos/química , Naftalenos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Piridinas/química , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
Assuntos
Disfunção Erétil/tratamento farmacológico , Fosfodiesterase I/metabolismo , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Purinas/síntese química , Purinas/uso terapêutico , 3',5'-GMP Cíclico Fosfodiesterases , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Piperazinas/farmacologia , Purinas/química , Ratos , Citrato de Sildenafila , Relação Estrutura-Atividade , Sulfonas , Vasodilatadores/síntese química , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêuticoRESUMO
Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).
Assuntos
3',5'-GMP Cíclico Fosfodiesterases/antagonistas & inibidores , Sistemas de Liberação de Medicamentos/métodos , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/enzimologia , Guanina/química , Inibidores de Fosfodiesterase/química , 3',5'-GMP Cíclico Fosfodiesterases/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Guanina/administração & dosagem , Humanos , Masculino , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/uso terapêutico , Compostos Policíclicos/administração & dosagem , Compostos Policíclicos/química , Relação Estrutura-AtividadeRESUMO
We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.5 nM, PDE6/PDE5=7).
Assuntos
Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Xantinas/síntese química , Xantinas/farmacologia , 3',5'-GMP Cíclico Fosfodiesterases , Alquilação , Animais , Área Sob a Curva , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Desenho de Fármacos , Estimulação Elétrica , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Pênis/efeitos dos fármacos , Piperazinas/farmacologia , Purinas , Coelhos , Citrato de Sildenafila , Relação Estrutura-Atividade , SulfonasRESUMO
The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.
Assuntos
Piperazinas/síntese química , Piperazinas/metabolismo , Receptores Muscarínicos/metabolismo , Sítios de Ligação , Ligantes , Estrutura Molecular , Piperazinas/química , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Relação Estrutura-AtividadeRESUMO
Himbacine (1), a complex piperidine alkaloid isolated from the bark of Australian magnolias, is a promising lead in Alzheimer's disease research due to its potent muscarinic receptor antagonist property. We have described here a highly efficient synthetic strategy that resulted in the total synthesis of himbacine (1) in about 10% overall yield and isohimbacine (1a), an unnatural isomer of himbacine, in 18% overall yield. The total synthesis of himbacine was initially approached using an intramolecular Diels-Alder reaction as the key step to generate intermediate 5 followed by a [3 + 2] cycloaddition with nitrone 4 to produce the isoxazolidine derivative 3. Methylation followed by catalytic reduction of 3 gave 12'-hydroxyhimbacine (20), which, upon dehydration, gave isohimbacine (1a) as the sole product. In an alternative approach, an all-encompassing intramolecular Diels-Alder reaction of an appropriately substituted tetraene derivative 31, which bears the entire latent carbon framework and functional group substitution of himbacine, gave the desired advanced tricyclic intermediate 33, which was readily converted to (+)-himbeline (2) and (+)-himbacine (1).