Progress in medicinal chemistry最新文献_第4页

Discovery and Development of Calcimimetic and Calcilytic Compounds. 石灰化和石灰化化合物的发现和发展。

Progress in medicinal chemistry Pub Date : 2018-01-01 Epub Date: 2018-03-13 DOI: 10.1016/bs.pmch.2017.12.001

Edward F Nemeth, Bradford C Van Wagenen, Manuel F Balandrin

{"title":"Discovery and Development of Calcimimetic and Calcilytic Compounds.","authors":"Edward F Nemeth, Bradford C Van Wagenen, Manuel F Balandrin","doi":"10.1016/bs.pmch.2017.12.001","DOIUrl":"https://doi.org/10.1016/bs.pmch.2017.12.001","url":null,"abstract":"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.","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2017.12.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36029508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 33

Big Data in Drug Discovery. 药物发现中的大数据。

Progress in medicinal chemistry Pub Date : 2018-01-01 Epub Date: 2018-02-24 DOI: 10.1016/bs.pmch.2017.12.003

Nathan Brown, Jean Cambruzzi, Peter J Cox, Mark Davies, James Dunbar, Dean Plumbley, Matthew A Sellwood, Aaron Sim, Bryn I Williams-Jones, Magdalena Zwierzyna, David W Sheppard

引用次数: 33

Recent Progress in the Discovery and Development of Small-Molecule Modulators of CFTR. CFTR小分子调节剂的发现与开发进展。

Progress in medicinal chemistry Pub Date : 2018-01-01 Epub Date: 2018-02-19 DOI: 10.1016/bs.pmch.2018.01.001

Phil R Kym, Xueqing Wang, Mathieu Pizzonero, Steven E Van der Plas

{"title":"Recent Progress in the Discovery and Development of Small-Molecule Modulators of CFTR.","authors":"Phil R Kym, Xueqing Wang, Mathieu Pizzonero, Steven E Van der Plas","doi":"10.1016/bs.pmch.2018.01.001","DOIUrl":"https://doi.org/10.1016/bs.pmch.2018.01.001","url":null,"abstract":"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.","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2018.01.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36029511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 24

Preface. 前言。

Progress in medicinal chemistry Pub Date : 2018-01-01 DOI: 10.1016/S0079-6468(18)30010-9

David R Witty, Brian Cox

引用次数: 0

VMAT2 Inhibitors and the Path to Ingrezza (Valbenazine). VMAT2抑制剂和Ingrezza (Valbenazine)通路。

Progress in medicinal chemistry Pub Date : 2018-01-01 Epub Date: 2018-03-07 DOI: 10.1016/bs.pmch.2017.12.002

Nicole D Harriott, John P Williams, Evan B Smith, Haig P Bozigian, Dimitri E Grigoriadis

{"title":"VMAT2 Inhibitors and the Path to Ingrezza (Valbenazine).","authors":"Nicole D Harriott, John P Williams, Evan B Smith, Haig P Bozigian, Dimitri E Grigoriadis","doi":"10.1016/bs.pmch.2017.12.002","DOIUrl":"https://doi.org/10.1016/bs.pmch.2017.12.002","url":null,"abstract":"The dopaminergic system plays a key role in the central nervous system, regulating executive function, arousal, reward, and motor control. Dysregulation of this critical monoaminergic system has been associated with diseases of the central nervous system including schizophrenia, Parkinson's disease, and disorders such as attention deficit hyperactivity disorders and addiction. Drugs that modify the dopaminergic system by modulating the activity of dopamine have been successful in demonstrating clinical efficacy by providing treatments for these diseases. Specifically, antipsychotics, both typical and atypical, while acting on a number of monoaminergic systems in the brain, primarily target the dopamine system via inhibition of postsynaptic dopamine receptors. The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Despite acting on opposing sides of the synapse, both antipsychotics and VMAT2 inhibitors act to decrease the activity of central dopaminergic systems. Tardive dyskinesia is a disorder characterized by involuntary repetitive movements and thought to be a result of a hyperdopaminergic state precipitated by the use of antipsychotics. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2 through an active metabolite, has been developed for the treatment of tardive dyskinesia and is the first drug approved for the treatment of this disorder. This chapter describes the process leading to the discovery of valbenazine, its pharmacological characteristics, along with preclinical and clinical evidence of its efficacy.","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2017.12.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36032402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

Enabling Chemistry Technologies and Parallel Synthesis-Accelerators of Drug Discovery Programmes. 使能化学技术和平行合成-药物发现计划的加速器。

Progress in medicinal chemistry Pub Date : 2017-01-01 Epub Date: 2017-02-10 DOI: 10.1016/bs.pmch.2016.11.001

A Vasudevan, A R Bogdan, H F Koolman, Y Wang, S W Djuric

引用次数: 12

Small Molecule Inhibition of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4). 白细胞介素-1受体相关激酶4 (IRAK4)的小分子抑制作用

Progress in medicinal chemistry Pub Date : 2017-01-01 Epub Date: 2017-02-14 DOI: 10.1016/bs.pmch.2016.11.004

N E Genung, K M Guckian

引用次数: 16

Development of LRRK2 Inhibitors for the Treatment of Parkinson's Disease. LRRK2抑制剂治疗帕金森病的研究进展

Progress in medicinal chemistry Pub Date : 2017-01-01 Epub Date: 2017-01-04 DOI: 10.1016/bs.pmch.2016.11.002

K V Christensen, G P Smith, D S Williamson

引用次数: 18

Recent Progress in the Discovery and Development of TRPA1 Modulators. TRPA1调制剂的研究进展。

Progress in medicinal chemistry Pub Date : 2017-01-01 Epub Date: 2017-02-06 DOI: 10.1016/bs.pmch.2016.11.003

S Skerratt

{"title":"Recent Progress in the Discovery and Development of TRPA1 Modulators.","authors":"S Skerratt","doi":"10.1016/bs.pmch.2016.11.003","DOIUrl":"https://doi.org/10.1016/bs.pmch.2016.11.003","url":null,"abstract":"TRPA1 is a well-validated therapeutic target in areas of high unmet medical need that include pain and respiratory disorders. The human genetic rationale for TRPA1 as a pain target is provided by a study describing a rare gain-of-function mutation in TRPA1, causing familial episodic pain syndrome. There is a growing interest in the TRPA1 field, with many pharmaceutical companies reporting the discovery of TRPA1 chemical matter; however, GRC 17536 remains to date the only TRPA1 antagonist to have completed Phase IIa studies. A key issue in the progression of TRPA1 programmes is the identification of high-quality orally bioavailable molecules. Most published TRPA1 ligands are commonly not suitable for clinical progression due to low lipophilic efficiency and/or poor absorption, distribution, metabolism, excretion and pharmaceutical properties. The recent TRPA1 cryogenic electron microscopy structure from the Cheng and Julius labs determined the structure of full-length human TRPA1 at up to 4Å resolution in the presence of TRPA1 ligands. This ground-breaking science paves the way to enable structure-based drug design within the TRPA1 field.","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2016.11.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34831309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 26

Preface. 前言。

Progress in medicinal chemistry Pub Date : 2017-01-01 DOI: 10.1016/S0079-6468(17)30016-4

D R Witty, B Cox

引用次数: 0