Progress in medicinal chemistry最新文献_第2页

Advances in the design of new types of inhaled medicines. 新型吸入药物的设计进展。

Progress in medicinal chemistry Pub Date : 2022-01-01 Epub Date: 2022-06-02 DOI: 10.1016/bs.pmch.2022.04.001

Werngard Czechtizky, Wu Su, Lena Ripa, Stefan Schiesser, Andreas Höijer, Rhona J Cox

{"title":"Advances in the design of new types of inhaled medicines.","authors":"Werngard Czechtizky, Wu Su, Lena Ripa, Stefan Schiesser, Andreas Höijer, Rhona J Cox","doi":"10.1016/bs.pmch.2022.04.001","DOIUrl":"https://doi.org/10.1016/bs.pmch.2022.04.001","url":null,"abstract":"Inhalation of small molecule drugs has proven very efficacious for the treatment of respiratory diseases due to enhanced efficacy and a favourable therapeutic index compared with other dosing routes. It enables targeted delivery to the lung with rapid onset of therapeutic action, low systemic drug exposure, and thereby reduced systemic side effects. An increasing number of pharmaceutical companies and biotechs are investing in new modalities-for this review defined as therapeutic molecules with a molecular weight >800Da and therefore beyond usual inhaled small molecule drug-like space. However, our experience with inhaled administration of PROTACs, peptides, oligonucleotides (antisense oligonucleotides, siRNAs, miRs and antagomirs), diverse protein scaffolds, antibodies and antibody fragments is still limited. Investigating the retention and metabolism of these types of molecules in lung tissue and fluid will contribute to understanding which are best suited for inhalation. Nonetheless, the first such therapeutic molecules have already reached the clinic. This review will provide information on the physiology of healthy and diseased lungs and their capacity for drug metabolism. It will outline the stability, aggregation and immunogenicity aspects of new modalities, as well as recap on formulation and delivery aspects. It concludes by summarising clinical trial outcomes with inhaled new modalities based on information available at the end of 2021.","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"61 ","pages":"93-162"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40400187","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: 3

The importance of plasma protein and tissue binding in a drug discovery program to successfully deliver a preclinical candidate. 血浆蛋白和组织结合在药物发现项目中对成功交付临床前候选药物的重要性。

Progress in medicinal chemistry Pub Date : 2022-01-01 Epub Date: 2022-06-06 DOI: 10.1016/bs.pmch.2022.04.002

Elizabeth Hann, Karine Malagu, Andrew Stott, Huw Vater

引用次数: 2

Hearing loss drug discovery and medicinal chemistry: Current status, challenges, and opportunities. 听力损失药物的发现和药物化学:现状、挑战和机遇。

Progress in medicinal chemistry Pub Date : 2022-01-01 Epub Date: 2022-06-07 DOI: 10.1016/bs.pmch.2022.05.001

Rick Cousins

{"title":"Hearing loss drug discovery and medicinal chemistry: Current status, challenges, and opportunities.","authors":"Rick Cousins","doi":"10.1016/bs.pmch.2022.05.001","DOIUrl":"https://doi.org/10.1016/bs.pmch.2022.05.001","url":null,"abstract":"Hearing loss is a severe high unmet need condition affecting more than 1.5 billion people globally. There are no licensed medicines for the prevention, treatment or restoration of hearing. Prosthetic devices, such as hearing aids and cochlear implants, do not restore natural hearing and users struggle with speech in the presence of background noise. Hearing loss drug discovery is immature, and small molecule approaches include repurposing existing drugs, combination therapeutics, late-stage discovery optimisation of known chemotypes for identified molecular targets of interest, phenotypic tissue screening and high-throughput cell-based screening. Hearing loss drug discovery requires the integration of specialist therapeutic area biology and otology clinical expertise. Small molecule drug discovery projects in the global clinical portfolio for hearing loss are here collated and reviewed. An overview is provided of human hearing, inner ear anatomy, inner ear delivery, types of hearing loss and hearing measurement. Small molecule experimental drugs in clinical development for hearing loss are reviewed, including their underpinning biology, discovery strategy and activities, medicinal chemistry, calculated physicochemical properties, pharmacokinetics and clinical trial status. SwissADME BOILED-Egg permeability modelling is applied to the molecules reviewed, and these results are considered. Non-small molecule hearing loss assets in clinical development are briefly noted in this review. Future opportunities in hearing loss drug discovery for human genomics and targeted protein degradation are highlighted.","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"61 ","pages":"1-91"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40400661","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: 3

Preface. 前言。

Progress in medicinal chemistry Pub Date : 2022-01-01 DOI: 10.1016/S0079-6468(22)00011-X

David R Witty, Brian Cox

引用次数: 0

Copyright 版权

Progress in medicinal chemistry Pub Date : 2021-01-01 DOI: 10.1016/s0079-6468(21)00010-2

引用次数: 0

Automated and enabling technologies for medicinal chemistry. 药物化学的自动化和使能技术。

Progress in medicinal chemistry Pub Date : 2021-01-01 Epub Date: 2021-06-07 DOI: 10.1016/bs.pmch.2021.01.003

Paula L Nichols

引用次数: 1

An industrial perspective on co-crystals: Screening, identification and development of the less utilised solid form in drug discovery and development. 共晶的工业前景:药物发现和开发中较少利用的固体形式的筛选、鉴定和开发。

Progress in medicinal chemistry Pub Date : 2021-01-01 Epub Date: 2021-06-08 DOI: 10.1016/bs.pmch.2021.05.001

Thomas Kendall, Sam Stratford, Adam R Patterson, Ruth A Lunt, Dyanne Cruickshank, Thierry Bonnaud, C Daniel Scott

{"title":"An industrial perspective on co-crystals: Screening, identification and development of the less utilised solid form in drug discovery and development.","authors":"Thomas Kendall, Sam Stratford, Adam R Patterson, Ruth A Lunt, Dyanne Cruickshank, Thierry Bonnaud, C Daniel Scott","doi":"10.1016/bs.pmch.2021.05.001","DOIUrl":"https://doi.org/10.1016/bs.pmch.2021.05.001","url":null,"abstract":"Active pharmaceutical ingredients are commonly marketed as a solid form due to ease of transport, storage and administration. In the design of a drug formulation, the selection of the solid form is incredibly important and is traditionally based on what polymorphs, hydrates or salts are available for that compound. Co-crystals, another potential solid form available, are currently not as readily considered as a viable solid form for the development process. Even though co-crystals are gaining an ever-increasing level of interest within the pharmaceutical community, their acceptance and application is still not as standard as other solid forms such as the ubiquitous pharmaceutical salt and stabilised amorphous formulations. Presented in this chapter is information that would allow for a co-crystal screen to be planned and conducted as well as scaled up using solution and mechanochemistry based methods commonly employed in both the literature and industry. Also presented are methods for identifying the formation of a co-crystal using a variety of analytical techniques as well as the importance of confirming the formation of co-crystals from a legal perspective and demonstrating the legal precedent by looking at co-crystalline products already on the market. The benefits of co-crystals have been well established, and presented in this chapter are a selection of examples which best exemplify their potential. The goal of this chapter is to increase the understanding of co-crystals and how they may be successfully exploited in early stage development.","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"60 ","pages":"345-442"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2021.05.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39249140","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: 1

Utilisation of compounds from venoms in drug discovery. 毒液化合物在药物发现中的应用。

Progress in medicinal chemistry Pub Date : 2021-01-01 Epub Date: 2021-03-27 DOI: 10.1016/bs.pmch.2021.01.001

Carol M Trim, Lee J Byrne, Steven A Trim

{"title":"Utilisation of compounds from venoms in drug discovery.","authors":"Carol M Trim, Lee J Byrne, Steven A Trim","doi":"10.1016/bs.pmch.2021.01.001","DOIUrl":"https://doi.org/10.1016/bs.pmch.2021.01.001","url":null,"abstract":"Difficult drug targets are becoming the normal course of business in drug discovery, sometimes due to large interacting surfaces or only small differences in selectivity regions. For these, a different approach is merited: compounds lying somewhere between the small molecule and the large antibody in terms of many properties including stability, biodistribution and pharmacokinetics. Venoms have evolved over millions of years to be complex mixtures of stable molecules derived from other somatic molecules, the stability comes from the pressure to be ready for delivery at a moment's notice. Snakes, spiders, scorpions, jellyfish, wasps, fish and even mammals have evolved independent venom systems with complex mixtures in their chemical arsenal. These venom-derived molecules have been proven to be useful tools, such as for the development of antihypotensive angiotensin converting enzyme (ACE) inhibitors and have also made successful drugs such as Byetta® (Exenatide), Integrilin® (Eptifibatide) and Echistatin. Only a small percentage of the available chemical space from venoms has been investigated so far and this is growing. In a new era of biological therapeutics, venom peptides present opportunities for larger target engagement surface with greater stability than antibodies or human peptides. There are challenges for oral absorption and target engagement, but there are venom structures that overcome these and thus provide substrate for engineering novel molecules that combine all desired properties. Venom researchers are characterising new venoms, species, and functions all the time, these provide great substrate for solving the challenges presented by today's difficult targets.","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"60 ","pages":"1-66"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2021.01.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39249136","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: 8

Preface. 前言。

Progress in medicinal chemistry Pub Date : 2021-01-01 DOI: 10.1016/S0079-6468(21)00013-8

David R Witty, Brian Cox

引用次数: 0

Use of molecular docking computational tools in drug discovery. 分子对接计算工具在药物发现中的应用。

Progress in medicinal chemistry Pub Date : 2021-01-01 Epub Date: 2021-05-27 DOI: 10.1016/bs.pmch.2021.01.004

Francesca Stanzione, Ilenia Giangreco, Jason C Cole

引用次数: 90