RESUMO
Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak µM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Desenho de Fármacos , Isoquinolinas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Tiofenos/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/química , Relação Estrutura-Atividade , Tiofenos/químicaRESUMO
The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico/química , Desenho de Fármacos , Isoquinolinas/farmacologia , Inibidores de Proteases/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Catálise , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Relação Estrutura-AtividadeRESUMO
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
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
The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction.
Assuntos
Encéfalo/metabolismo , MAP Quinase Quinase 4/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Administração Oral , Desenho de Fármacos , Ligação de Hidrogênio , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-AtividadeRESUMO
In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-ß in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.
Assuntos
Aminopiridinas/química , Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/química , Inibidores de Proteínas Quinases/química , Triazinas/química , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Animais , Sítios de Ligação , Sistema Nervoso Central/metabolismo , Simulação por Computador , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazinas/uso terapêuticoRESUMO
The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.
Assuntos
Encéfalo/metabolismo , Desenho de Fármacos , Degeneração Neural/prevenção & controle , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Tiofenos/farmacologia , Tiofenos/farmacocinética , Animais , Técnicas de Química Sintética , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Meia-Vida , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
From high throughput screening, we discovered compound 1, the prototype for a series of disubstituted thiophene inhibitors of JNK which is selective towards closely related MAP kinases p38 and Erk2. Herein we describe the evolution of these compounds to a novel class of thiophene and thiazole JNK inhibitors that retain favorable solubility, permeability, and P-gp properties for development as CNS agents for treatment of neurodegeneration. Compound 61 demonstrated JNK3 IC(50)=77 nM and retained the excellent broad kinase selectivity observed for the series.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Quinolinas/síntese química , Tiazóis/química , Tiofenos/química , Animais , Desenho de Fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologiaRESUMO
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αß by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etilaminas/síntese química , Etilaminas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Alquilação , Doença de Alzheimer , Animais , Encéfalo/metabolismo , Linhagem Celular , Cães , Desenho de Fármacos , Cobaias , Humanos , Indicadores e Reagentes , Inibidores de Proteases/farmacocinética , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship of the prime region of hydroxyethylamine BACE inhibitors is described. Variation in the aryl linker region with 5- and 6-membered heterocycles provided compounds such as 33 with improved permeability and reduced P-gp liability compared to benzyl amine analog 1.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Etilaminas/química , Etilaminas/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/química , Cristalografia por Raios X , Etilaminas/síntese química , Humanos , Modelos Moleculares , Inibidores de Proteases/síntese química , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
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
The structural modification of a series of [3.3.1] bicyclic sulfonamide based gamma-secretase inhibitors is described. Appropriate substitution on the bicyclic scaffold provides a significant increase in the metabolic stability of the compounds resulting in an improved in vivo metabolic profile.
Assuntos
Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Compostos Bicíclicos com Pontes/química , Inibidores de Proteases/química , Sulfonamidas/química , Doença de Alzheimer/tratamento farmacológico , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos com Pontes/uso terapêutico , Humanos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
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
By use of the effectively cleaved beta-secretase (BACE) substrate (1), incorporation of a statine in P(1) resulted in a weak inhibitor 13 of the enzyme. Further substitution of P(1)'-Asp by P(1)'-Val in 13 results in a potent inhibitor 22 of BACE. Removal of the P(10)-P(5) residues on the N-terminal part of inhibitor 22 resulted in no loss of potency (23). C-terminal truncations of inhibitor 22 generally led to significant loss of potency.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Oligopeptídeos/síntese química , Secretases da Proteína Precursora do Amiloide , Encéfalo/enzimologia , Endopeptidases , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Oligopeptídeos/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC(50) = 30 nM) toward BACE. Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.
Assuntos
Amidas/síntese química , Ácido Aspártico Endopeptidases/química , Dipeptídeos/química , Etilenos/síntese química , Ácidos Ftálicos/síntese química , Inibidores de Proteases/síntese química , Amidas/química , Secretases da Proteína Precursora do Amiloide , Desenho de Fármacos , Endopeptidases , Etilenos/química , Humanos , Modelos Moleculares , Mimetismo Molecular , Ácidos Ftálicos/química , Inibidores de Proteases/química , Relação Estrutura-AtividadeRESUMO
We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.
Assuntos
Aminoácidos/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Oligopeptídeos/química , Aminoácidos/química , Aminoácidos/farmacologia , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Linhagem Celular , Endopeptidases , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Mimetismo Molecular , Relação Estrutura-AtividadeRESUMO
We have prepared a series of bis-bidentate complexes of rhenium that mimic the size, shape, and peripheral functionality of steroidal androgens. In a model system, we used 2D NMR and X-ray crystallographic analysis to show that adjacent N-methyl and oxo substitutents adopt an anti configuration during the coordination reaction. We have synthesized a bis-bidentate oxorhenium(V) complex whose structure and peripheral functionality mimic 5alpha-dihydrotestosterone. 2D-NMR analysis indicates that the N-methyl and oxo substituents are driven into the steroidal anti configuration (beta-N-methyl, alpha-oxo) by the beta-orientation of the methyl group equivalent to C-18. Thus, this metal complex provides a remarkable structural and stereochemical mimic of a steroid. Its in vivo stability, however, appears to be limited.
RESUMO
Surface Plasmon Resonance (SPR) is rarely used as a primary High-throughput Screening (HTS) tool in fragment-based approaches. With SPR instruments becoming increasingly high-throughput it is now possible to use SPR as a primary tool for fragment finding. SPR becomes, therefore, a valuable tool in the screening of difficult targets such as the ubiquitin E3 ligase Parkin. As a prerequisite for the screen, a large number of SPR tests were performed to characterize and validate the active form of Parkin. A set of compounds was designed and used to define optimal SPR assay conditions for this fragment screen. Using these conditions, more than 5000 pre-selected fragments from our in-house library were screened for binding to Parkin. Additionally, all fragments were simultaneously screened for binding to two off target proteins to exclude promiscuous binding compounds. A low hit rate was observed that is in line with hit rates usually obtained by other HTS screening assays. All hits were further tested in dose responses on the target protein by SPR for confirmation before channeling the hits into Nuclear Magnetic Resonance (NMR) and other hit-confirmation assays.