RESUMO
This paper describes the rational design, synthesis, structure-activity relationship (SAR), and biological profile of presenilin-1 (PSEN-1) complex selective γ-secretase inhibitors, assessed for selectivity using a unique set of four γ-secretase subtype complexes. A set of known PSEN-1 selective γ-Secretase inhibitors (GSIs) was analyzed to understand the pharmacophoric features required for selective inhibition. Conformational modeling suggests that a characteristic 'U' shape orientation between aromatic sulfone/sulfonamide and aryl ring is crucial for PSEN-1 selectivity and potency. Using these insights, a series of brain-penetrant 2-azabicyclo[2,2,2]octane sulfonamides was devised and synthesized as a new class of PSEN-1 selective inhibitors. Compounds 13c and 13k displayed high potency towards PSEN1-APH1B complex but moderate selectivity towards PSEN2 complexes. However, compound (+)-13b displayed low nanomolar potency towards the PSEN1-APH1B complex, little (â¼4-fold) selectivity towards PSEN1-APH1A, and high selectivity (>350-fold) versus PSEN2 complexes. Excellent brain penetration, no significant CYP inhibition, or cardiotoxicity, good solubility, and permeability make (+)-13b an excellent candidate for further lead optimization.
Assuntos
Secretases da Proteína Precursora do Amiloide , Sulfonamidas , Sulfonamidas/farmacologia , Presenilina-1 , Octanos , Sulfanilamida , EncéfaloRESUMO
Clinical development of γ-secretases, a family of intramembrane cleaving proteases, as therapeutic targets for a variety of disorders including cancer and Alzheimer's disease was aborted because of serious mechanism-based side effects in the phase III trials of unselective inhibitors. Selective inhibition of specific γ-secretase complexes, containing either PSEN1 or PSEN2 as the catalytic subunit and APH1A or APH1B as supporting subunits, does provide a feasible therapeutic window in preclinical models of these disorders. We explore here the pharmacophoric features required for PSEN1 versus PSEN2 selective inhibition. We synthesized a series of brain penetrant 2-azabicyclo[2,2,2]octane sulfonamides and identified a compound with low nanomolar potency and high selectivity (>250-fold) toward the PSEN1-APH1B subcomplex versus PSEN2 subcomplexes. We used modeling and site-directed mutagenesis to identify critical amino acids along the entry part of this inhibitor into the catalytic site of PSEN1. Specific targeting one of the different γ-secretase complexes might provide safer drugs in the future.
Assuntos
Secretases da Proteína Precursora do Amiloide , Complexos Multiproteicos , Presenilina-1 , Sulfonamidas , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Presenilina-1/antagonistas & inibidores , Presenilina-1/metabolismo , Complexos Multiproteicos/antagonistas & inibidores , Complexos Multiproteicos/metabolismo , Sulfonamidas/farmacologia , Especificidade por Substrato , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/metabolismoRESUMO
We recently disclosed a set of heteroaryl-fused piperazine inhibitors of BACE1 that combined nanomolar potency with good intrinsic permeability and low Pgp-mediated efflux. Herein we describe further work on two prototypes of this family of inhibitors aimed at modulating their basicity and reducing binding to the human ether-a-go-go-related gene (hERG) channel. This effort has led to the identification of compound 36, a highly potent (hAß42 cell IC50 = 1.3 nM), cardiovascularly safe, and orally bioavailable compound that elicited sustained Aß42 reduction in mouse and dog animal models.
RESUMO
A common challenge for medicinal chemists is to reduce the pKa of strongly basic groups' conjugate acids into a range that preserves the desired effects, usually potency and/or solubility, but avoids undesired effects like high volume of distribution (Vd), limited membrane permeation, and off-target binding to, notably, the hERG channel and monoamine receptors. We faced this challenge with a 3,4,5,6-tetrahydropyridine-2-amine scaffold harboring an amidine, a key structural component of potential inhibitors of BACE1, the rate-limiting enzyme in the production of Aß species that make up amyloid plaques in Alzheimer's disease. In our endeavor to balance potency with desirable properties to achieve brain penetration, we introduced a diverse set of groups in beta position of the amidine that modulate logD, PSA and pKa. Given the synthetic challenge to prepare these highly functionalized warheads, we first developed a design flow including predicted physicochemical parameters which allowed us to select only the most promising candidates for synthesis. For this we evaluated a set of commercial packages to predict physicochemical properties, which can guide medicinal chemists in their endeavors to modulate pKa values of amidine and amine bases.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Elétrons , Inibidores Enzimáticos/farmacologia , Pirrolidinas/farmacologia , Amidinas/química , Amidinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Físico-Química , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-AtividadeRESUMO
The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid ß lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Descoberta de Drogas , Pirrolidinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-AtividadeRESUMO
ß-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is considered to be a promising target for treating Alzheimer's disease. However, all clinical BACE1 inhibitors have failed due to lack of efficacy, and some have even led to cognitive worsening. Recent evidence points to the importance of avoiding BACE2 inhibition along with careful dose titration. In this study, we focused on the fact that the 10s loop lining the S3 pocket in BACE1 can form both "open (up)" and "closed (down)" conformations, whereas in BACE2, it prefers to adopt a "closed" form; thus, more space is available in BACE1. By leveraging the difference, we designed fused pyridine analogues that could reach the 10s loop, leading to 6 with high selectivity and significant Aß reduction. The cocrystal structures confirmed that 6 significantly increased B-factors of the 10s loop in BACE2 relative to those in BACE1. Thus, the destabilization of BACE2 seems to offer structural insights into the reduced BACE2 potency of 6, explaining the significant improvement in BACE1 selectivity.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
BACE1 is an attractive target for disease-modifying treatment of Alzheimer's disease. BACE2, having high homology around the catalytic site, poses a critical challenge to identifying selective BACE1 inhibitors. Recent evidence indicated that BACE2 has various roles in peripheral tissues and the brain, and therefore, the chronic use of nonselective inhibitors may cause side effects derived from BACE2 inhibition. Crystallographic analysis of the nonselective inhibitor verubecestat identified explicit water molecules with different levels of free energy in the S2' pocket. Structure-based design targeting them enabled the identification of propynyl oxazine 3 with improved selectivity. Further optimization efforts led to the discovery of compound 6 with high selectivity. The cocrystal structures of 7, a close analogue of 6, bound to BACE1 and BACE2 confirmed that one of the explicit water molecules is displaced by the propynyl group, suggesting that the difference in the relative water displacement cost may contribute to the improved selectivity.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/metabolismo , Desenho de Fármacos , Humanos , Oxazinas/química , Oxazinas/farmacologia , Relação Estrutura-Atividade , Água/químicaRESUMO
INTRODUCTION: Inhibition of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) has been extensively pursued as potential disease-modifying treatment for Alzheimer's disease (AD). Clinical failures with BACE inhibitors have progressively raised the bar forever cleaner candidates with reduced cardiovascular liability, toxicity risk, and increased selectivity over cathepsin D (CatD) and BACE2. AREAS COVERED: This review provides an overview of patented BACE1 inhibitors between 2011 and 2020 per pharmaceutical company or research group and highlights the progress that was made in dialing out toxicity liabilities. EXPERT OPINION: Despite an increasingly crowded IP situation, significant progress was made using highly complex chemistry in avoiding toxicity liabilities, with BACE1/BACE2 selectivity being the most remarkable achievement. However, clinical trial data suggest on-target toxicity is likely a contributing factor, which implies the only potential future of BACE1 inhibitors lies in careful titration of highly selective compounds in early populations where the amyloid burden is still minimal as prophylactic therapy, or as an affordable oral maintenance therapy following amyloid-clearing therapies.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Desenvolvimento de Medicamentos , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Humanos , Patentes como Assunto , Inibidores de Proteases/farmacologiaRESUMO
The ß-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as ß-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aß reduction in dog even at 0.16â mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [14 C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1â mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Oxazinas/farmacologia , Tiazinas/farmacologia , Secretases da Proteína Precursora do Amiloide/deficiência , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/deficiência , Ácido Aspártico Endopeptidases/metabolismo , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Oxazinas/química , Ratos , Relação Estrutura-Atividade , Tiazinas/administração & dosagem , Tiazinas/químicaRESUMO
Genetic evidence points to deposition of amyloid-ß (Aß) as a causal factor for Alzheimer's disease. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Aß reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Aß reduction of 80% at trough level.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/química , Tiazinas/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Meia-Vida , Haplorrinos , Coração/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Ratos , Ratos Sprague-Dawley , Tiazinas/metabolismo , Tiazinas/farmacologiaRESUMO
Despite several years of research, only a handful of ß-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.
RESUMO
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Indóis/síntese química , Desenho de Fármacos , Humanos , Relação Estrutura-AtividadeRESUMO
BACE1 inhibitors hold potential as agents in disease-modifying treatment for Alzheimer's disease. BACE2 cleaves the melanocyte protein PMEL in pigment cells of the skin and eye, generating melanin pigments. This role of BACE2 implies that nonselective and chronic inhibition of BACE1 may cause side effects derived from BACE2. Herein, we describe the discovery of potent and selective BACE1 inhibitors using structure-based drug design. We targeted the flap region, where the shape and flexibility differ between these enzymes. Analysis of the cocrystal structures of an initial lead 8 prompted us to incorporate spirocycles followed by its fine-tuning, culminating in highly selective compounds 21 and 22. The structures of 22 bound to BACE1 and BACE2 revealed that a relatively high energetic penalty in the flap of the 22-bound BACE2 structure may cause a loss in BACE2 potency, thereby leading to its high selectivity. These findings and insights should contribute to responding to the challenges in exploring selective BACE1 inhibitors.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Biotransformação , Desenho de Fármacos , Descoberta de Drogas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos/metabolismo , Modelos Moleculares , Fármacos Neuroprotetores/farmacocinética , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors offer the potential of disease-modifying treatment for Alzheimer's disease (AD). Since 2014, major breakthroughs have appeared in the field of BACE1 inhibitors. This review provides an overview of amidine-based BACE1 inhibitors between 2014 and 2018. Herein are summarized i) the structure-activity relationship, ii) the physiological results and iii) the potential risks from a lack of selectivity. This review also summarizes clinical scope, results and outlook of the compounds that have been or are currently under development in clinical trials.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Amidinas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Heterocíclicos/uso terapêutico , Inibidores de Proteases/química , Amidinas/química , Animais , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
ß-Secretase (BACE1) has an essential role in the production of amyloid ß peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in 24 with robust Aß reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Oxazinas/química , Oxazinas/farmacologia , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Simulação de Acoplamento Molecular , Oxazinas/metabolismo , Oxazinas/farmacocinética , Conformação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p Ka of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aß levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF3-group, which reduced hERG inhibition. This has led to compound 3, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Administração Intravenosa , Administração Oral , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Ácido Aspártico Endopeptidases/metabolismo , Disponibilidade Biológica , Doenças Cardiovasculares/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Canal de Potássio ERG1/metabolismo , Cobaias , Humanos , Masculino , Camundongos Endogâmicos , Oxazinas/química , Fragmentos de Peptídeos/líquido cefalorraquidiano , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Accumulation of Aß peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. ß-Secretase (BACE1) is a key enzyme responsible for producing Aß peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydrooxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a p Ka lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Aß reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models. This compound improved the brain-to-plasma ratio relative to 6 by reducing P-gp recognition, which was demonstrated by a P-gp knockout mouse model.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Oxazinas/química , Fragmentos de Peptídeos/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Secretases da Proteína Precursora do Amiloide/química , Animais , Ácido Aspártico Endopeptidases/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cristalografia por Raios X , Cães , Desenho de Fármacos , Canal de Potássio ERG1/metabolismo , Cobaias , Humanos , Células Madin Darby de Rim Canino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxazinas/farmacologia , Inibidores de Proteases/farmacocinética , Relação Estrutura-AtividadeRESUMO
Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors hold great potential as disease modifying anti-Alzheimer's drugs. This digest provides an overview of the amidine containing class of BACE1 inhibitors, of which multiple examples are now progressing through clinical trials. The various structural modifications highlight the struggle to combine potency with the optimal properties for a brain penetrant BACE1 inhibitor, and illustrate the crowded competitive landscape. This overview concludes with a summary of potential issues including substrate and target selectivity and a synopsis of the status of the current and past clinical assets.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Amidinas/farmacologia , Amidinas/farmacocinética , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/metabolismo , Doença de Alzheimer/metabolismo , Amidinas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/efeitos dos fármacos , Descoberta de Drogas/métodos , Humanos , Modelos MolecularesRESUMO
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aß42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.