Pub Date : 2023-01-01Epub Date: 2023-11-14DOI: 10.1016/bs.pmch.2023.10.002
Matilda Bingham, Thomas Pesnot, Andrew D Scott
In the last two decades the use of biophysical assays and methods in medicinal chemistry has increased significantly, to meet the demands of the novel targets and modalities that drug discoverers are looking to tackle. The desire to obtain accurate affinities, kinetics, thermodynamics and structural data as early as possible in the drug discovery process has fuelled this innovation. This review introduces the principles underlying the techniques in common use and provides a perspective on the weaknesses and strengths of different methods. Case studies are used to further illustrate some of the applications in medicinal chemistry and a discussion of the emerging biophysical methods on the horizon is presented.
{"title":"Biophysical screening and characterisation in medicinal chemistry.","authors":"Matilda Bingham, Thomas Pesnot, Andrew D Scott","doi":"10.1016/bs.pmch.2023.10.002","DOIUrl":"10.1016/bs.pmch.2023.10.002","url":null,"abstract":"<p><p>In the last two decades the use of biophysical assays and methods in medicinal chemistry has increased significantly, to meet the demands of the novel targets and modalities that drug discoverers are looking to tackle. The desire to obtain accurate affinities, kinetics, thermodynamics and structural data as early as possible in the drug discovery process has fuelled this innovation. This review introduces the principles underlying the techniques in common use and provides a perspective on the weaknesses and strengths of different methods. Case studies are used to further illustrate some of the applications in medicinal chemistry and a discussion of the emerging biophysical methods on the horizon is presented.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138047829","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}
Pub Date : 2023-01-01Epub Date: 2023-11-14DOI: 10.1016/bs.pmch.2023.10.001
Adrian D Hobson
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.
{"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":"<p><p>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.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"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}
Pub Date : 2023-01-01Epub Date: 2023-11-13DOI: 10.1016/bs.pmch.2023.10.003
Brad Hocking, Alan Armstrong, David J Mann
As the development of drugs with a covalent mode of action is becoming increasingly popular, well-validated covalent fragment-based drug discovery (FBDD) methods have been comparatively slow to keep up with the demand. In this chapter the principles of covalent fragment reactivity, library design, synthesis, and screening methods are explored in depth, focussing on literature examples with direct applications to practical covalent fragment library design and screening. Further, questions about the future of the field are explored and potential useful advances are proposed.
{"title":"Covalent fragment libraries in drug discovery-Design, synthesis, and screening methods.","authors":"Brad Hocking, Alan Armstrong, David J Mann","doi":"10.1016/bs.pmch.2023.10.003","DOIUrl":"10.1016/bs.pmch.2023.10.003","url":null,"abstract":"<p><p>As the development of drugs with a covalent mode of action is becoming increasingly popular, well-validated covalent fragment-based drug discovery (FBDD) methods have been comparatively slow to keep up with the demand. In this chapter the principles of covalent fragment reactivity, library design, synthesis, and screening methods are explored in depth, focussing on literature examples with direct applications to practical covalent fragment library design and screening. Further, questions about the future of the field are explored and potential useful advances are proposed.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138047830","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}
Pub Date : 2022-01-01Epub Date: 2022-06-02DOI: 10.1016/bs.pmch.2022.04.001
Werngard Czechtizky, Wu Su, Lena Ripa, Stefan Schiesser, Andreas Höijer, Rhona J Cox
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.
{"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":"<p><p>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.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"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}
Pub Date : 2022-01-01Epub Date: 2022-06-06DOI: 10.1016/bs.pmch.2022.04.002
Elizabeth Hann, Karine Malagu, Andrew Stott, Huw Vater
Plasma protein binding and tissue binding are arguably two of the most critical parameters that are measured as part of a drug discovery program since, according to the free drug hypothesis, it is the free drug that is responsible for both efficacy and toxicity. This chapter aims to deconstruct the role of plasma protein and tissue binding in drug discovery programs, and to consider the conclusion made by Pfizer and Genentech/Depomed a decade ago that optimising plasma protein binding as an independent parameter does not significantly influence efficacy. This chapter will also examine how binding metrics are applied in drug discovery programs and explore circumstances where optimising plasma protein or tissue binding can be an effective strategy to deliver a candidate molecule for preclinical development with an early indication of sufficient therapeutic index.
{"title":"The importance of plasma protein and tissue binding in a drug discovery program to successfully deliver a preclinical candidate.","authors":"Elizabeth Hann, Karine Malagu, Andrew Stott, Huw Vater","doi":"10.1016/bs.pmch.2022.04.002","DOIUrl":"https://doi.org/10.1016/bs.pmch.2022.04.002","url":null,"abstract":"<p><p>Plasma protein binding and tissue binding are arguably two of the most critical parameters that are measured as part of a drug discovery program since, according to the free drug hypothesis, it is the free drug that is responsible for both efficacy and toxicity. This chapter aims to deconstruct the role of plasma protein and tissue binding in drug discovery programs, and to consider the conclusion made by Pfizer and Genentech/Depomed a decade ago that optimising plasma protein binding as an independent parameter does not significantly influence efficacy. This chapter will also examine how binding metrics are applied in drug discovery programs and explore circumstances where optimising plasma protein or tissue binding can be an effective strategy to deliver a candidate molecule for preclinical development with an early indication of sufficient therapeutic index.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40400662","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}
Pub Date : 2022-01-01Epub Date: 2022-06-07DOI: 10.1016/bs.pmch.2022.05.001
Rick Cousins
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.
{"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":"<p><p>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.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"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}
Pub Date : 2022-01-01DOI: 10.1016/S0079-6468(22)00011-X
David R Witty, Brian Cox
{"title":"Preface.","authors":"David R Witty, Brian Cox","doi":"10.1016/S0079-6468(22)00011-X","DOIUrl":"https://doi.org/10.1016/S0079-6468(22)00011-X","url":null,"abstract":"","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40400188","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}
Pub Date : 2021-01-01DOI: 10.1016/s0079-6468(21)00010-2
{"title":"Copyright","authors":"","doi":"10.1016/s0079-6468(21)00010-2","DOIUrl":"https://doi.org/10.1016/s0079-6468(21)00010-2","url":null,"abstract":"","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/s0079-6468(21)00010-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"55877993","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}
Pub Date : 2021-01-01Epub Date: 2021-06-07DOI: 10.1016/bs.pmch.2021.01.003
Paula L Nichols
Having always been driven by the need to get new treatments to patients as quickly as possible, drug discovery is a constantly evolving process. This chapter will review how medicinal chemistry was established, how it has changed over the years due to the emergence of new enabling technologies, and how early advances in synthesis, purification and analysis, have provided the foundations upon which the current automated and enabling technologies are built. Looking beyond the established technologies, this chapter will also consider technologies that are now emerging, and their impact on the future of drug discovery and the role of medicinal chemists.
{"title":"Automated and enabling technologies for medicinal chemistry.","authors":"Paula L Nichols","doi":"10.1016/bs.pmch.2021.01.003","DOIUrl":"https://doi.org/10.1016/bs.pmch.2021.01.003","url":null,"abstract":"<p><p>Having always been driven by the need to get new treatments to patients as quickly as possible, drug discovery is a constantly evolving process. This chapter will review how medicinal chemistry was established, how it has changed over the years due to the emergence of new enabling technologies, and how early advances in synthesis, purification and analysis, have provided the foundations upon which the current automated and enabling technologies are built. Looking beyond the established technologies, this chapter will also consider technologies that are now emerging, and their impact on the future of drug discovery and the role of medicinal chemists.</p>","PeriodicalId":20755,"journal":{"name":"Progress in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/bs.pmch.2021.01.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39249137","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}