RESUMO
In this paper we describe our strategy to improve the aqueous solubility of SCH 900229, a potent PS1-selective γ-secretase inhibitor for the treatment of Alzheimer's disease. Incorporation of ionizable amino groups into the side chain terminal generates water soluble ß-aminosulfone analogues of SCH 900229 that maintain robust in vitro potency and in vivo efficacy.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzopiranos/química , Benzopiranos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Benzopiranos/farmacocinética , Cães , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Humanos , Ratos , Solubilidade , Sulfonas/farmacocinética , Água/químicaRESUMO
Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Guanina/farmacologia , Xantinas/farmacologia , Animais , Glicemia/efeitos dos fármacos , Cristalografia por Raios X , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Guanina/análogos & derivados , Guanina/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Xantinas/administração & dosagem , Xantinas/químicaRESUMO
The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-ß (Aß) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD).
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Morfolinas/química , Morfolinas/farmacologia , Sulfonamidas/química , Doença de Alzheimer/tratamento farmacológico , Animais , Inibidores Enzimáticos/uso terapêutico , Feminino , Masculino , Camundongos , Morfolinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-ß (Aß) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Descoberta de Drogas/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Disponibilidade Biológica , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inibidores Enzimáticos/farmacocinética , Células HEK293 , Humanos , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Assuntos
Inibidores Enzimáticos/farmacologia , Iminas/farmacologia , Pirimidinonas/farmacologia , Renina/antagonistas & inibidores , Administração Oral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Iminas/síntese química , Iminas/química , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/química , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
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
In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Azepinas/síntese química , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Animais , Azepinas/química , Azepinas/farmacologia , Canal de Potássio ERG1 , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
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
Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aß40-42, compared to their parent compounds.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzopiranos/química , Inibidores Enzimáticos/química , Sulfonas/química , Benzopiranos/síntese química , Benzopiranos/farmacologia , Benzoquinonas/síntese química , Benzoquinonas/química , Benzoquinonas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Flúor/química , Flúor/farmacologia , Humanos , Estrutura Molecular , Oxirredução , Sulfonas/síntese química , Sulfonas/farmacologiaRESUMO
An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aß40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aß after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.
RESUMO
Fused oxadiazines (3) were discovered as selective and orally bioavailable γ-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure-activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds 8r and 8s that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall γ-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound 8s confirm that the oxadiazine series of compounds are potent GSMs.
RESUMO
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
SAR exploration at C-6 and C-8 positions of the tricyclic sulfone series was carried out. Several functional groups were found to be well tolerated at C-6 and C-8 positions. Selective combination of C-6 and C-8 modification resulted in new tricyclic sulfone analogs with efficacy in in vivo mouse Aß(40) lowering model.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Sulfonas/síntese química , Sulfonas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Ciclização , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Fragmentos de Peptídeos/metabolismo , Relação Estrutura-Atividade , Sulfonas/químicaRESUMO
We herein report the discovery of four series of fused 5,6-bicyclic heterocycles as γ-secretase modulators. Synthesis and SAR of these series are discussed. These compounds represent a new class of γ-secretase modulators that demonstrate moderate to good in vitro potency in inhibiting Aß(42) production.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
Design and synthesis of cis-2,6-disubstituted N-arylsulfonyl morpholines as novel γ-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. Several different small alkyl groups are installed on the left-hand side to lower the CYP3A4 liability while maintaining excellent in vitro potency.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Morfolinas/síntese química , Morfolinas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/química , Morfolinas/química , Relação Estrutura-AtividadeRESUMO
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
Tricyclic sulfones were designed as gamma-secretase inhibitors and found to have excellent potency. Extensive SAR shows that a large number of sulfonamides at position 7 of the tricycle are very well tolerated. Compounds such as 15a and 15c showed remarkable in vivo potency.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Sulfonas/química , Sulfonas/farmacologia , Administração Oral , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/sangue , Animais , Química Encefálica/efeitos dos fármacos , Camundongos , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonas/síntese químicaRESUMO
A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Receptores Notch/efeitos dos fármacos , Sulfonas/química , Sulfonas/farmacologia , Animais , Cristalografia por Raios X , Desenho de Fármacos , Camundongos , Modelos Moleculares , Sulfonas/síntese químicaRESUMO
A new class of 2,6-disubstituted morpholine N-arylsulfonamide gamma-secretase inhibitors was designed based on the introduction of a morpholine core in lieu or piperidine in our lead series. This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Abeta levels in Tg CRND8 mice upon oral administration were identified.