RESUMO
Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Receptor Muscarínico M1/agonistas , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Animais , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Inibidores da Colinesterase/farmacologia , Cricetulus , Cristalização , Modelos Animais de Doenças , Cães , Donepezila/farmacologia , Eletroencefalografia , Feminino , Células HEK293 , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Simulação de Dinâmica Molecular , Degeneração Neural/complicações , Degeneração Neural/patologia , Primatas , Ratos , Receptor Muscarínico M1/química , Transdução de Sinais , Homologia Estrutural de ProteínaRESUMO
Optimisation of a series of pyrazole inhibitors of the human FPR1 receptor has been achieved. The use of an in vitro media loss assay was utilised to identify sub-series with more robust DMPK profiles. These were subsequently improved to generate analogues with attractive overall profiles.
Assuntos
Pirazóis/síntese química , Pirazóis/farmacologia , Receptores de Formil Peptídeo/antagonistas & inibidores , Animais , Química Farmacêutica/métodos , Físico-Química/métodos , Desenho de Fármacos , Hepatócitos/citologia , Humanos , Concentração Inibidora 50 , Masculino , Microssomos Hepáticos/metabolismo , Modelos Químicos , Ratos , Ratos Sprague-Dawley , Receptores de Formil Peptídeo/químicaRESUMO
The optimization of a new series of muscarinic M(3) antagonists is described, leading to the identification of AZD9164 which was progressed into the clinic for evaluation of its potential as a treatment for COPD.
Assuntos
Antagonistas Muscarínicos/química , Piperidinas/química , Quinuclidinas/química , Receptor Muscarínico M3/agonistas , Proteínas Sanguíneas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ligação Proteica , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/farmacologia , Quinuclidinas/uso terapêutico , Receptor Muscarínico M3/metabolismo , Relação Estrutura-AtividadeRESUMO
N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high-throughput screen (HTS) of a subset of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs.
RESUMO
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.