ABSTRACT
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.
Subject(s)
Alzheimer Disease/drug therapy , Drug Design , Receptor, Muscarinic M1/agonists , Aged , Aged, 80 and over , Aging/pathology , Alzheimer Disease/complications , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Amino Acid Sequence , Animals , Blood Pressure/drug effects , CHO Cells , Cholinesterase Inhibitors/pharmacology , Cricetulus , Crystallization , Disease Models, Animal , Dogs , Donepezil/pharmacology , Electroencephalography , Female , HEK293 Cells , Heart Rate/drug effects , Humans , Male , Mice, Inbred C57BL , Models, Molecular , Molecular Dynamics Simulation , Nerve Degeneration/complications , Nerve Degeneration/pathology , Primates , Rats , Receptor, Muscarinic M1/chemistry , Signal Transduction , Structural Homology, ProteinABSTRACT
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.
ABSTRACT
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.
Subject(s)
Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, Formyl Peptide/antagonists & inhibitors , Animals , Chemistry, Pharmaceutical/methods , Chemistry, Physical/methods , Drug Design , Hepatocytes/cytology , Humans , Inhibitory Concentration 50 , Male , Microsomes, Liver/metabolism , Models, Chemical , Rats , Rats, Sprague-Dawley , Receptors, Formyl Peptide/chemistryABSTRACT
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.
Subject(s)
Muscarinic Antagonists/chemistry , Piperidines/chemistry , Quinuclidines/chemistry , Receptor, Muscarinic M3/agonists , Blood Proteins/metabolism , Drug Evaluation, Preclinical , Humans , Muscarinic Antagonists/pharmacology , Muscarinic Antagonists/therapeutic use , Piperidines/pharmacology , Piperidines/therapeutic use , Protein Binding , Pulmonary Disease, Chronic Obstructive/drug therapy , Quinuclidines/pharmacology , Quinuclidines/therapeutic use , Receptor, Muscarinic M3/metabolism , Structure-Activity RelationshipABSTRACT
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.
