Progress in medicinal chemistry最新文献

Natural products have a long-standing and critical role in drug development and medical use. The structural and physicochemical properties of natural products, while derived evolutionarily to be effective in living systems, may create challenges in translation to a pharmaceutical product. Molecular complexity, low solubility, functional group reactivity and general instability are among the challenges that typically need to be overcome. This review looks at some of the ways that natural products have been formulated and delivered to enable the successful application of these vitally important medicines to patients.

Amyotrophic lateral sclerosis (ALS) is caused by selective and progressive loss of spinal, bulbar and cortical motoneurons and leads to irreversible paralysis, loss of speech, inability to swallow and respiratory malfunctions with the eventual death of the affected individual in a rapid disease course. Several suggested molecular pathways are reviewed including SOD1 gene mutation, protein nitrosylation, phosphorylation and oxidative stress, excitotoxicity, glutamate transporter deprivation, mitochondrial involvement, protein aggregation and motor neuron trophic factors. The role of insulin and its receptor in the brain is described. It is very possible that in 90% of the sporadic ALS cases, the cause of the motor neuron degeneration is different or that multiple mechanisms are involved that would need drugs with multiple mechanisms or action. Several marketed drugs have been selected for clinical trials. Only two drugs have been approved by the FDA as showing positive effect in ALS: Riluzole and Edaravone. Two other drugs that have a significant benefit in ALS are Talampanel and Tamoxifen. The results for modulation of the neurotrophic factor Insulin Growth Factor-1 (IGF1) as a potential treatment are inconclusive. Several compounds are discussed that show a positive effect in the mouse model but which have failed in clinical trials. New approaches using different modalities such as peptides, proteins and stem cells are promising. Our ability to design better drugs would be enhanced by investigating the endogenous factors in neuron death, protein aggregation and oxidative stress that would improve our understanding of the potential pathways that result in neurodegeneration.

This chapter will discuss the recent literature of macrocycles and drug-like property space moving beyond the rule of five (bRo5). Trends in chemical classes that fall within this definition are discussed and the impact of the latest technologies in the field assessed. The physicochemical properties, which have provided both successes and challenges, especially in scale-up, are discussed. A recent patent literature is reviewed and the chapter concludes with a perspective on the future of macrocyclic drug discovery.

The extracellular calcium receptor (CaR) is a G protein-coupled receptor (GPCR) and the pivotal molecule regulating systemic Ca²⁺ homeostasis. The CaR was a challenging target for drug discovery because its physiological ligand is an inorganic ion (Ca²⁺) rather than a molecule so there was no structural template to guide medicinal chemistry. Nonetheless, small molecules targeting this receptor were discovered. Calcimimetics are agonists or positive allosteric modulators of the CaR, while calcilytics are antagonists and all to date are negative allosteric modulators. The calcimimetic cinacalcet was the first allosteric modulator of a GPCR to achieve regulatory approval and is a first-in-class treatment for secondary hyperparathyroidism in patients on dialysis, and for hypercalcemia in some forms of primary hyperparathyroidism. It is also useful in treating some rare genetic diseases that cause hypercalcemia. Two other calcimimetics are now on the market (etelcalcetide) or under regulatory review (evocalcet). Calcilytics stimulate the secretion of parathyroid hormone and were initially developed as treatments for osteoporosis. Three different calcilytics of two different chemotypes failed in clinical trials due to lack of efficacy. Calcilytics are now being repurposed and might be useful in treating hypoparathyroidism and several rare genetic diseases causing hypocalcemia. The challenges ahead for medicinal chemists are to design compounds that select conformations of the CaR that preferentially target a particular signalling pathway and/or that affect the CaR in a tissue-selective manner.

Interpretation of Big Data in the drug discovery community should enhance project timelines and reduce clinical attrition through improved early decision making. The issues we encounter start with the sheer volume of data and how we first ingest it before building an infrastructure to house it to make use of the data in an efficient and productive way. There are many problems associated with the data itself including general reproducibility, but often, it is the context surrounding an experiment that is critical to success. Help, in the form of artificial intelligence (AI), is required to understand and translate the context. On the back of natural language processing pipelines, AI is also used to prospectively generate new hypotheses by linking data together. We explain Big Data from the context of biology, chemistry and clinical trials, showcasing some of the impressive public domain sources and initiatives now available for interrogation.

Cystic fibrosis (CF) is a genetic disorder driven by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. While different mutations lead to varying levels of disease severity, the most common CFTR F508del mutation leads to defects in protein stability, trafficking to the cell membrane and gating of chloride ions. Recently, advances in medicinal chemistry have led to the identification small-molecule drugs that result in significant clinical efficacy in improving lung function in CF patients. Multiple CFTR modulators are required to fix the various defects in the CFTR protein. Small-molecule potentiators increase the open-channel probability and improve the gating of ions through CFTR. Small-molecule correctors stabilize the protein fold of the mutant channel, facilitating protein maturation and translocation to the cellular membrane. Recent data suggest that triple-combination therapy consisting of a potentiator and two correctors that operate through distinct mechanisms will be required to deliver highly significant clinical efficacy for most CF patients. The progress in medicinal chemistry that has led to the identification of novel CFTR potentiators and correctors is presented in this chapter.