RESUMEN
In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes the synthetic approach demonstrated on largest scale for each new drug based on patent or primary literature. The synthetic routes highlight practical methods to construct molecules, sometimes on the manufacturing scale, to access the new drugs. Ten additional drugs approved in 2021 and one approved in 2020 are included that were not covered in the previous year's review.
Asunto(s)
Aprobación de Drogas , Estados Unidos , Japón , United States Food and Drug Administration , ChinaRESUMEN
Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.
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Diseño de Fármacos , Humanos , Preparaciones Farmacéuticas , Inmunoconjugados/químicaRESUMEN
New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.
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Diseño de Fármacos , Inmunoconjugados , HumanosRESUMEN
Increasing saturation (Fsp3) remains a central strategy in the optimization of properties of molecules during drug discovery. Here, we describe a versatile and operationally simple one-pot procedure for accomplishing this goal via a nucleophilic aromatic substitution-decarboxylation sequence to construct C(sp2)-C(sp3) bonds. The method is tolerant of a variety of biologically privileged moieties and has been demonstrated in a library format.
Asunto(s)
DescarboxilaciónRESUMEN
New drugs introduced to the market are privileged structures having affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This review is part of a continuing series presenting the most likely process-scale synthetic approaches to 40 NCEs approved for the first time anywhere in the world in 2019.
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Técnicas de Química Sintética/métodos , Compuestos Orgánicos/síntesis química , Preparaciones Farmacéuticas/síntesis química , Animales , HumanosRESUMEN
Heterobifunctional chimeric degraders are a class of ligands that recruit target proteins to E3 ubiquitin ligases to drive compound-dependent protein degradation. Advancing from initial chemical tools, protein degraders represent a mechanism of growing interest in drug discovery. Critical to the mechanism of action is the formation of a ternary complex between the target, degrader and E3 ligase to promote ubiquitination and subsequent degradation. However, limited insights into ternary complex structures exist, including a near absence of studies on one of the most widely co-opted E3s, cellular inhibitor of apoptosis 1 (cIAP1). In this work, we use a combination of biochemical, biophysical and structural studies to characterize degrader-mediated ternary complexes of Bruton's tyrosine kinase and cIAP1. Our results reveal new insights from unique ternary complex structures and show that increased ternary complex stability or rigidity need not always correlate with increased degradation efficiency.
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Agammaglobulinemia Tirosina Quinasa/genética , Proteínas Inhibidoras de la Apoptosis/genética , Cromatografía en Gel , Reactivos de Enlaces Cruzados , Humanos , Cinética , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Conformación Proteica , Proteolisis , Espectrometría de Masa por Ionización de Electrospray , Ubiquitina-Proteína Ligasas , Ubiquitinación , Difracción de Rayos XRESUMEN
New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 39 new chemical entities approved for the first time globally in 2018.
Asunto(s)
Aprobación de Drogas , Preparaciones Farmacéuticas/química , Descubrimiento de Drogas , Historia del Siglo XXI , Estructura MolecularRESUMEN
New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 31 new chemical entities approved for the first time globally in 2017.
Asunto(s)
Aprobación de Drogas , Diseño de Fármacos , Modelos Químicos , Preparaciones Farmacéuticas/síntesis química , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Fármacos Gastrointestinales/síntesis química , Fármacos Gastrointestinales/química , Fármacos Hematológicos/síntesis química , Fármacos Hematológicos/química , Estructura Molecular , Soluciones Oftálmicas/síntesis química , Soluciones Oftálmicas/química , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/clasificaciónRESUMEN
New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 19 new chemical entities that were approved for the first time in 2016.
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Aprobación de Drogas/historia , Preparaciones Farmacéuticas/historia , Diseño de Fármacos , Historia del Siglo XXI , Estructura Molecular , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/químicaRESUMEN
New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 29 new chemical entities (NCEs) that were approved for the first time in 2015.
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Descubrimiento de Drogas/métodos , Preparaciones Farmacéuticas/síntesis química , Antiinfecciosos/síntesis química , Antiinflamatorios no Esteroideos/síntesis química , Antineoplásicos/síntesis química , Fármacos Cardiovasculares/síntesis química , Fármacos del Sistema Nervioso Central/síntesis química , Técnicas de Química Sintética , Fármacos Gastrointestinales/síntesis química , Hipoglucemiantes/síntesis química , Receptores de Trombopoyetina/agonistasRESUMEN
As part of our efforts to develop new classes of tubulin inhibitor payloads for antibody-drug conjugate (ADC) programs, we developed a tubulysin ADC that demonstrated excellent in vitro activity but suffered from rapid metabolism of a critical acetate ester. A two-pronged strategy was employed to address this metabolism. First, the hydrolytically labile ester was replaced by a carbamate functional group resulting in a more stable ADC that retained potency in cellular assays. Second, site-specific conjugation was employed in order to design ADCs with reduced metabolic liabilities. Using the later approach, we were able to identify a conjugate at the 334C position of the heavy chain that resulted in an ADC with considerably reduced metabolism and improved efficacy. The examples discussed herein provide one of the clearest demonstrations to-date that site of conjugation can play a critical role in addressing metabolic and PK liabilities of an ADC. Moreover, a clear correlation was identified between the hydrophobicity of an ADC and its susceptibility to metabolic enzymes. Importantly, this study demonstrates that traditional medicinal chemistry strategies can be effectively applied to ADC programs.
RESUMEN
The tubulysin class of natural products has attracted much attention from the medicinal chemistry community due to its potent cytotoxicity against a wide range of human cancer cell lines, including significant activity in multidrug-resistant carcinoma models. As a result of their potency, the tubulysins have become an important tool for use in targeted therapy, being widely pursued as payloads in the development of novel small molecule drug conjugates (SMDCs) and antibody-drug conjugates (ADCs). A structure-based and parallel medicinal chemistry approach was applied to the synthesis of novel tubulysin analogues. These efforts led to the discovery of a number of novel and potent cytotoxic tubulysin analogues, providing a framework for our simultaneous report, which highlights the discovery of tubulysin-based ADCs, including use of site-specific conjugation to address in vivo stability of the C-11 acetate functionality.
RESUMEN
The total synthesis of the Strychnos alkaloid (±)-minfiensine was achieved via an intramolecular amidofuran Diels-Alder cycloaddition/rearrangement followed by an iminium ion/cyclization cascade sequence. This domino process provides for a rapid access to the unique 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole core structure found in the alkaloid minfiensine (2). In this paper, the full account of our synthetic study is described, highlighting the successful application of the cascade sequence to form the A/B/C/D rings of (±)-minfiensine (2) in high yield. A palladium-catalyzed enolate coupling reaction was then used to furnish the final E ring and complete the total synthesis of (±)-minfiensine (2).
RESUMEN
New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of thirty-seven NCEs that were approved for the first time in 2014 and one drug which was approved in 2013 and was not covered in a previous edition of this review.
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Diseño de Fármacos , Comercio , Industria FarmacéuticaRESUMEN
New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of twenty-four NCEs that were approved for the first time in 2013 and two 2012 drugs which were not covered during the previous edition of this review.
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Preparaciones Farmacéuticas/síntesis química , Diseño de Fármacos , Estructura Molecular , Preparaciones Farmacéuticas/químicaRESUMEN
Dolastatin 10 is a powerful antineoplastic agent and microtubule inhibitor that was discovered by Pettit et al. and published in 1987. Since then, many research groups have engaged in SAR studies of synthetic analogues, termed "auristatins". It was eventually discovered that auristatins are of great value as payloads in antibody drug conjugates (ADCs), which led to the FDA-approved ADC brentuximab vedotin (Seattle Genetics). Currently, over 30 ADCs in clinical trials employ auristatins as payloads, and there is a great interest in the research community, both on academic and industrial sides, to further study these analogues. This review will provide an overview of the recent advancements in auristatin development spanning a time frame of about the past ten years. The main focus will be to describe structural changes made to the auristatin peptide and their resulting biological activities in tumor cell proliferation assays. Selected ADC examples will also be described.
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Aminobenzoatos/química , Inmunoconjugados/química , Oligopéptidos/química , Brentuximab Vedotina , Depsipéptidos/químicaRESUMEN
Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with α,α-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design.
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Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Depsipéptidos/química , Depsipéptidos/farmacología , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Animales , Área Bajo la Curva , Células Cultivadas , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Ratas , Ratas Wistar , Relación Estructura-Actividad , Espectrometría de Masas en Tándem , Tubulina (Proteína)/metabolismoRESUMEN
New drugs introduced to the market every year represent a privileged structure for a particular biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011.
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Preparaciones Farmacéuticas/síntesis química , Estructura Molecular , Preparaciones Farmacéuticas/químicaRESUMEN
Dyotropic rearrangements of fused, tricyclic ß-lactones are described that proceed via unprecedented stereospecific, 1,2-acyl migrations delivering bridged, spiro-γ-butyrolactones. A unique example of this dyotropic process involves a fused bis-lactone possessing both ß- and δ-lactone moieties which enabled rapid access to the core structures of curcumanolide A and curcumalactone. Our current mechanistic understanding of the latter dyotropic process, based on computational studies, is also described. Other key transformations in the described divergent syntheses of (-)-curcumanolide A and (-)-curcumalactone from a common intermediate (11 and 12 steps from 2-methyl-1,3-cyclopentanedione, respectively), include a catalytic, asymmetric nucleophile (Lewis base)-catalyzed aldol-lactonization (NCAL) leading to a tricyclic ß-lactone, a Baeyer-Villiger oxidation in the presence of a ß-lactone, and highly facial-selective and stereocomplementary reductions of an intermediate spirocyclic enoate. The described dyotropic rearrangements significantly alter the topology of the starting tricyclic ß-lactone, providing access to complex spirocyclic cyclopentyl-γ-lactones and bis-γ-lactones in a single synthetic operation.