RESUMO
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
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridazinas/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-AtividadeRESUMO
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Quinolinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Quinolinas/síntese química , Quinolinas/química , 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
Leucine rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetration.
Assuntos
Compostos Heterocíclicos com 2 Anéis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Amidas/metabolismo , Animais , Sítios de Ligação , Células HEK293 , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Camundongos , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , TransfecçãoRESUMO
The preparation of novel tetrahydro-1H-pyrazolo[4,3-c]pyridines is reported. Pivotal to the synthesis of these compounds was the development of mild reaction conditions to generate a highly functionalized nitrilimine capable of undergoing an intramolecular cycloaddition with a tethered alkyne. The desired cycloadduct was formed as an equal mixture of diastereomers.
Assuntos
Ciclização , Iminas/química , Nitrilas/química , Piridinas/síntese química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos MolecularesRESUMO
Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D- and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure-activity data of the training set indicate that the 2' position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3' or 4' positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3' and 4' position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3',4'-benzo analog, 79. A complementary 2D-QSAR approach-partial least squares analysis using a reduced set of Molconn-Z descriptors-supports the CoMFA structure-activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl)acetate, an analog not in the original data set, to be in good agreement with the experimental value.
Assuntos
Metilfenidato/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Isomerismo , Metilfenidato/síntese química , Metilfenidato/farmacologia , Modelos Moleculares , Ligação Proteica , Relação Quantitativa Estrutura-AtividadeRESUMO
Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Piperidinas/química , Sulfonamidas/química , Animais , Descoberta de Drogas , Estabilidade de Medicamentos , Microssomos Hepáticos/metabolismo , Piperidinas/síntese química , Piperidinas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
Discovery of a series of pyrazolopiperidine sulfonamide based gamma-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Piperidinas/química , Piperidinas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Humanos , Camundongos , Modelos Moleculares , Piperidinas/uso terapêutico , Relação Estrutura-Atividade , Sulfonamidas/uso terapêuticoRESUMO
A series of threo-1-aza-3 or 4-substituted-5-phenyl[4.4.0]decanes (quinolizidines), which were envisioned as restricted rotational analogues (RRAs) of methylphenidate (MP), was synthesized and tested for inhibitory potency against [(3)H]WIN35,428, [3H]citalopram, and [3H]nisoxetine binding to the dopamine, serotonin, and norepinephrine transporters, respectively. Two different synthetic schemes were used; a Wittig reaction or acylation (followed by an intramolecular condensation) was a key feature of each scheme. The unsubstituted RRA, threo(trans)-1-aza-5-phenyl[4.4.0]decane (12a), was equipotent to unconstrained threo-MP against [(3)H]WIN35,428 binding. The extra ring in these RRAs (which reduces the conformational freedom) and the orientation and polarity of substituents at the 4-position on this extra ring are of critical importance to the biological activity. Generally, the RRAs paralleled the corresponding unconstrained MP derivatives in binding affinity to the three transporters. The results suggest that the conformation of MP in which the carbonyl group of the methyl ester is H-bonded to the piperidinyl N-H may be the bioactive form of the molecule.