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1.
J Med Chem ; 61(8): 3491-3502, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29617572

RESUMO

BACE1 is responsible for the first step in APP proteolysis, leading to toxic Aß production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles. Selective BACE1 inhibitors were found to exhibit two distinct conformational features proximal to the flap and the S3 subpocket. Several new molecules were designed and tested to make use of this observation. The combination of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in lead molecule 28, which exhibited ∼50-fold selectivity. Compared to a nonselective BACE1/2 inhibitor, 28 showed significantly less inhibition of PMEL processing in human melanocytes, indicating good functional selectivity of this inhibitor class.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/química , Encéfalo/metabolismo , Domínio Catalítico , Cães , Feminino , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Oxazóis/farmacocinética , Oxazóis/farmacologia , Fragmentos de Peptídeos/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/química , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Antígeno gp100 de Melanoma/metabolismo
2.
Drug Discov Today ; 22(12): 1844-1850, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28916303

RESUMO

Flow cytometry is a technology providing multiparametric analysis of single cells or other suspension particles. High-throughput (HT) flow cytometry has become an attractive screening platform for drug discovery. In this review, we highlight the recent HT flow cytometry applications, and then focus on HT flow cytometry deployment at AstraZeneca (AZ). Practical considerations for successful HT flow cytometry assay development and screening are provided based on experience from four project case studies at AZ. We provide an overview of the scientific rationale, explain why HT flow cytometry was chosen and how HT flow cytometry assays deliver new ways to support the drug discovery process.


Assuntos
Descoberta de Drogas , Citometria de Fluxo , Ensaios de Triagem em Larga Escala , Humanos
3.
J Alzheimers Dis ; 50(4): 1109-23, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26890753

RESUMO

A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-ß peptide (Aß) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-ß protein precursor (AßPP) to Aß peptides, with the soluble N terminal fragment of AßPP (sAßPPß) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aß. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aß40, Aß42, and sAßPPß. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aß. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacocinética , Administração Oral , Peptídeos beta-Amiloides/metabolismo , Animais , Análise Química do Sangue , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/enzimologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Cobaias , Humanos , Cinética , Masculino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/metabolismo
4.
J Chem Inf Model ; 54(3): 818-25, 2014 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-24456077

RESUMO

Scoring potency is a main challenge for structure based drug design. Inductive effects of subtle variations in the ligand are not possible to accurately predict by classical computational chemistry methods. In this study, the problem of predicting potency of ligands with electronic variations participating in key interactions with the protein was addressed. The potency was predicted for a large set of cyclic amidine and guanidine cores extracted from ß-secretase (BACE-1) inhibitors. All cores were of similar size and had equal interaction motifs but were diverse with respect to electronic substitutions. A density functional theory approach, in combination with a representation of the active site of a protein using only key residues, was shown to be predictive. This computational approach was used to guide and support drug design, within the time frame of a normal drug discovery design cycle.


Assuntos
Amidinas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Guanidina/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Amidinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Biologia Computacional , Inibidores Enzimáticos/farmacologia , Guanidina/farmacologia , Humanos , Modelos Biológicos , Modelos Moleculares
5.
Thromb Res ; 132(2): 248-55, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23830061

RESUMO

INTRODUCTION: Oral treatment is lacking for haemophilia, the rare bleeding disorders, and some severe forms of von Willebrand's disease. We have serendipitously identified a small molecule procoagulant compound (AZ10047130). This publication describes some characteristics of AZ10047130 and a systematic search for novel hits using a, human plasma-based, high-throughput screening (HTS) assay. MATERIAL AND METHODS: Coagulation, thrombin generation, chromogenic assays and surface plasmon resonance (SPR) experiments were used to characterise AZ10047130. A 1536-well formatted human plasma coagulation assay for HTS was developed. RESULTS: In the plasma clot assay (re-calcified plasma with low tissue factor) AZ10047130 shortened time to coagulation with an EC50 value of 3.9 µM (assay concentration). AZ10047130 was similarly effective in immunodepleted human and haemophilia A plasmas. SPR and chromogenic substrate experiments indicated that AZ10047130 binds to the heparin binding site of several coagulation factors. The HTS screened in excess of one million compounds. It generated some hits belonging to the same pharmacophore as AZ10047130 but also some entirely novel hits. CONCLUSION: These novel small molecule procoagulant compounds may serve as templates for discovery of oral procoagulant drugs.


Assuntos
Benzofuranos/farmacologia , Análise Química do Sangue/métodos , Fatores de Coagulação Sanguínea/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Sulfonamidas/farmacologia , Benzofuranos/química , Fatores de Coagulação Sanguínea/química , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Hemostasia/efeitos dos fármacos , Humanos , Sulfonamidas/química , Trombina/biossíntese
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