RESUMO
A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described.
Assuntos
Antirreumáticos/farmacologia , Integrina alfa4beta1/antagonistas & inibidores , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antirreumáticos/administração & dosagem , Antirreumáticos/síntese química , Artrite Experimental/tratamento farmacológico , Asma/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Colágeno Tipo II/antagonistas & inibidores , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Fibronectinas/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Conformação Molecular , Esclerose Múltipla/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/síntese químicaRESUMO
The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Cromanos/química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Sítios de Ligação , Células Cultivadas , Etilaminas/síntese química , Etilaminas/química , Etilaminas/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Camundongos , Pirazóis/química , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats.
Assuntos
Integrina alfa4/química , Polietilenoglicóis/química , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Ésteres , Meia-Vida , Humanos , Injeções Subcutâneas , Integrina alfa4/imunologia , Integrina alfa4/metabolismo , Células Jurkat , RatosRESUMO
Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.
Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Administração Oral , Animais , Encéfalo/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Células HEK293 , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/síntese química , Pteridinas/química , Pteridinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Quinase 1 Polo-LikeRESUMO
A series of potent α4ß1/α4ß7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn's disease.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Integrinas/antagonistas & inibidores , Administração Oral , Animais , Área Sob a Curva , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Modelos Animais de Doenças , Meia-Vida , Humanos , Integrina alfa4beta1/metabolismo , Integrinas/metabolismo , Células Jurkat , Microssomos Hepáticos/metabolismo , RatosRESUMO
To improve wayfinding in hospitals or other complex buildings a prototype of an indoor navigation app was implemented that uses Augmented Reality for positioning and guiding users. The iOS and Android app allow the navigation from anywhere inside an area of 690 m2. In a usability test 8 from 12 users preferred using the app over a map or verbal directions. Along with the proposed improvements this approach allows covering areas as large as 100'000 m2.
Assuntos
Realidade Aumentada , HospitaisRESUMO
Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2' position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.
Assuntos
Acetamidas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Butanóis/química , Cicloexilaminas/química , Inibidores de Proteases/química , Acetamidas/síntese química , Acetamidas/farmacocinética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Butanóis/síntese química , Butanóis/farmacocinética , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Cicloexilaminas/síntese química , Cicloexilaminas/farmacocinética , Humanos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Relação Estrutura-AtividadeRESUMO
Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Desenho de Fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/genética , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/genética , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
In this Letter, we report our strategy to design potent and metabolically stable gamma-secretase inhibitors that are efficacious in reducing the cortical Abetax-40 levels in FVB mice via a single PO dose.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/síntese química , Pirazóis/química , Quinolinas/química , Sulfonamidas/química , Administração Oral , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Desenho de Fármacos , Camundongos , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The design and synthesis of a novel series of potent and cell permeable peptidomimetic inhibitors of the human beta-secretase (BACE) are described. These inhibitors feature a hydroxyethyl secondary amine isostere and a novel aromatic ring replacement for the C-terminus. The crystal structure of BACE in complex with this hydroxyethyl secondary amine isostere inhibitor is also presented.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Modelos Moleculares , Peptídeos/química , Ácidos Ftálicos/síntese química , Precursor de Proteína beta-Amiloide/química , Linhagem Celular , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Mimetismo Molecular , Estrutura Molecular , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacologia , EstereoisomerismoRESUMO
Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition inâ vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.
Assuntos
Encéfalo/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , alfa-Sinucleína/metabolismo , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Feminino , Células HEK293 , Meia-Vida , Humanos , Masculino , Camundongos , Simulação de Dinâmica Molecular , Fosforilação/efeitos dos fármacos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-DawleyRESUMO
Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aß generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aß generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aß in the CSF of healthy human volunteers.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Pirazóis/farmacologia , Quinolinas/farmacologia , Receptores Notch/antagonistas & inibidores , Sulfonamidas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Animais , Área Sob a Curva , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Estabilidade de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/química , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Notch/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Fatores de Tempo , Fatores de Transcrição HES-1RESUMO
INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering Aß production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aß40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aß production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aß was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aß reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aß production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aß in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aß was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.