Progress in medicinal chemistry最新文献

To homeostasis and beyond! Recent advances in the medicinal chemistry of heterobifunctional derivatives. 平衡与超越！杂官能团衍生物药物化学的最新进展。

Progress in medicinal chemistry Pub Date : 2024-01-01 Epub Date: 2024-09-19 DOI: 10.1016/bs.pmch.2024.07.002

Diana Castagna, Benoit Gourdet, Roland Hjerpe, Philip MacFaul, Andrew Novak, Guillaume Revol, Etienne Rochette, Allan Jordan

引用次数: 0

Harnessing conformational drivers in drug design. 在药物设计中利用构象驱动因素。

Progress in medicinal chemistry Pub Date : 2024-01-01 Epub Date: 2024-09-14 DOI: 10.1016/bs.pmch.2024.07.001

Praful Chovatia, Angelo Sanzone, Gert-Jan Hofman, Ruth Dooley, Bernardo Pezzati, Iuni Margaret Laura Trist, Gilles Ouvry

引用次数: 0

Another decade of antimalarial drug discovery: New targets, tools and molecules. 抗疟药物发现的又一个十年：新目标、新工具和新分子

Progress in medicinal chemistry Pub Date : 2024-01-01 Epub Date: 2024-09-26 DOI: 10.1016/bs.pmch.2024.08.001

John G Woodland, André Horatscheck, Candice Soares de Melo, Godwin A Dziwornu, Dale Taylor

{"title":"Another decade of antimalarial drug discovery: New targets, tools and molecules.","authors":"John G Woodland, André Horatscheck, Candice Soares de Melo, Godwin A Dziwornu, Dale Taylor","doi":"10.1016/bs.pmch.2024.08.001","DOIUrl":"https://doi.org/10.1016/bs.pmch.2024.08.001","url":null,"abstract":"Malaria remains a devastating but preventable infectious disease that disproportionately affects the African continent. Emerging resistance to current frontline therapies means that not only are new treatments urgently required, but also novel validated antimalarial targets to circumvent cross-resistance. Fortunately, tremendous efforts have been made by the global drug discovery community over the past decade. In this chapter, we will highlight some of the antimalarial drug discovery and development programmes currently underway across the globe, charting progress in the identification of new targets and the development of new classes of drugs to prosecute them. These efforts have been complemented by the development of valuable tools to accelerate target validation such as the NOD scid gamma (NSG) humanized mouse efficacy model and progress in predictive modelling and open-source software. Among the medicinal chemistry programmes that have been conducted over the past decade are those targeting Plasmodium falciparum ATPase4 (ATP4) and acetyl-CoA synthetase (AcAS) as well as proteins disrupting parasite protein translation such as the aminoacyl-tRNA synthetases (aaRSs) and eukaryotic elongation factor 2 (eEF2). The benefits and challenges of targeting Plasmodium kinases will be examined, with a focus on Plasmodium cyclic GMP-dependent protein kinase (PKG), cyclin-dependent-like protein kinase 3 (CLK3) and phosphatidylinositol 4-kinase (PI4K). The chapter concludes with a survey of incipient drug discovery centres in Africa and acknowledges the value of recent international meetings in galvanizing and uniting the antimalarial drug discovery community.","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"63 1","pages":"161-234"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381563","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: 0

Biophysical screening and characterisation in medicinal chemistry. 药物化学中的生物物理筛选和表征。

Progress in medicinal chemistry Pub Date : 2023-01-01 Epub Date: 2023-11-14 DOI: 10.1016/bs.pmch.2023.10.002

Matilda Bingham, Thomas Pesnot, Andrew D Scott

引用次数: 0

Antibody drug conjugates beyond cytotoxic payloads. 抗体药物偶联超出细胞毒性有效载荷。

Progress in medicinal chemistry Pub Date : 2023-01-01 Epub Date: 2023-11-14 DOI: 10.1016/bs.pmch.2023.10.001

Adrian D Hobson

{"title":"Antibody drug conjugates beyond cytotoxic payloads.","authors":"Adrian D Hobson","doi":"10.1016/bs.pmch.2023.10.001","DOIUrl":"10.1016/bs.pmch.2023.10.001","url":null,"abstract":"For many years, antibody drug conjugates (ADC) have teased with the promise of targeted payload delivery to diseased cells, embracing the targeting of the antibody to which a cytotoxic payload is conjugated. During the past decade this promise has started to be realised with the approval of more than a dozen ADCs for the treatment of various cancers. Of these ADCs, brentuximab vedotin really laid the foundations of a template for a successful ADC with lysosomal payload release from a cleavable dipeptide linker, measured DAR by conjugation to the Cys-Cys interchain bonds of the antibody and a cytotoxic payload. Using this ADC design model oncology has now expanded their repertoire of payloads to include non-cytotoxic compounds. These new payload classes have their origins in prior medicinal chemistry programmes aiming to design selective oral small molecule drugs. While this may not have been achieved, the resulting compounds provide excellent starting points for ADC programmes with some compounds amenable to immediate linker attachment while for others extensive SAR and structural information offer invaluable design insights. Many of these new oncology payload classes are of interest to other therapeutic areas facilitating rapid access to drug-linkers for exploration as non-oncology ADCs. Other therapeutic areas have also pursued unique payload classes with glucocorticoid receptor modulators (GRM) being the most clinically advanced in immunology. Here, ADC payloads come full circle, as oncology is now investigating GRM payloads for the treatment of cancer. This chapter aims to cover all these new ADC approaches while describing the medicinal chemistry origins of the new non-cytotoxic payloads.","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":"62 ","pages":"1-59"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138047828","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: 0

Covalent fragment libraries in drug discovery-Design, synthesis, and screening methods. 共价片段文库在药物发现中的应用——设计、合成和筛选方法。

Progress in medicinal chemistry Pub Date : 2023-01-01 Epub Date: 2023-11-13 DOI: 10.1016/bs.pmch.2023.10.003

Brad Hocking, Alan Armstrong, David J Mann

引用次数: 0

Preface. 前言。

Progress in medicinal chemistry Pub Date : 2023-01-01 DOI: 10.1016/S0079-6468(23)00011-5

Jonathan Bentley, Matilda Bingham

引用次数: 0

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