ABSTRACT
Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.
Subject(s)
Drug Design , Receptors, Vitronectin , Animals , Rats , Humans , Receptors, Vitronectin/antagonists & inhibitors , Receptors, Vitronectin/metabolism , Structure-Activity Relationship , Liver Cirrhosis/drug therapy , Models, Molecular , Drug Discovery , Rats, Sprague-Dawley , Male , Crystallography, X-Ray , Benzimidazoles/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesisABSTRACT
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.
Subject(s)
Drug Approval , United States , Japan , United States Food and Drug Administration , ChinaABSTRACT
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.
Subject(s)
Drug Design , Humans , Pharmaceutical Preparations , Immunoconjugates/chemistryABSTRACT
Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.
ABSTRACT
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.
Subject(s)
Drug Design , Immunoconjugates , HumansABSTRACT
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.
Subject(s)
Chemistry Techniques, Synthetic/methods , Organic Chemicals/chemical synthesis , Pharmaceutical Preparations/chemical synthesis , Animals , HumansABSTRACT
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.
Subject(s)
Drug Approval , Pharmaceutical Preparations/chemistry , Drug Discovery , History, 21st Century , Molecular StructureABSTRACT
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.
Subject(s)
Drug Approval , Drug Design , Models, Chemical , Pharmaceutical Preparations/chemical synthesis , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Gastrointestinal Agents/chemical synthesis , Gastrointestinal Agents/chemistry , Hematologic Agents/chemical synthesis , Hematologic Agents/chemistry , Molecular Structure , Ophthalmic Solutions/chemical synthesis , Ophthalmic Solutions/chemistry , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/classificationABSTRACT
The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.
Subject(s)
Drug Design , Drug Inverse Agonism , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Pyridines/administration & dosage , Pyridines/pharmacology , Administration, Oral , Animals , Biological Availability , Drug Evaluation, Preclinical , Humans , Mice , Pyridines/pharmacokinetics , Th17 Cells/drug effects , Th17 Cells/metabolismABSTRACT
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.
Subject(s)
Drug Approval/history , Pharmaceutical Preparations/history , Drug Design , History, 21st Century , Molecular Structure , Pharmaceutical Preparations/chemical synthesis , Pharmaceutical Preparations/chemistryABSTRACT
Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).
Subject(s)
CREB-Binding Protein/antagonists & inhibitors , Drug Design , E1A-Associated p300 Protein/antagonists & inhibitors , Morpholines/pharmacology , CREB-Binding Protein/metabolism , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , E1A-Associated p300 Protein/metabolism , Humans , Molecular Structure , Morpholines/chemical synthesis , Morpholines/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Drug Discovery/methods , Pharmaceutical Preparations/chemical synthesis , Anti-Infective Agents/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cardiovascular Agents/chemical synthesis , Central Nervous System Agents/chemical synthesis , Chemistry Techniques, Synthetic , Gastrointestinal Agents/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Receptors, Thrombopoietin/agonistsABSTRACT
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.
Subject(s)
Drug Design , Commerce , Drug IndustryABSTRACT
Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor. In addition, the CBP bromodomain inhibitor modulated the mRNA level of the regulator of G-protein signaling 4 (RGS4) gene in neurons, suggesting a potential therapeutic opportunity for CBP inhibitors in the treatment of neurological disorders.
Subject(s)
CREB-Binding Protein/antagonists & inhibitors , Drug Design , Small Molecule Libraries/chemistry , CREB-Binding Protein/genetics , Fluorescence Resonance Energy Transfer , Gene Expression Regulation/drug effects , Humans , Protein Structure, Tertiary , RGS Proteins/genetics , Small Molecule Libraries/pharmacology , TranscriptomeABSTRACT
A versatile synthesis of 7-azaindoles from substituted 2-fluoropyridines is described. C3-metalation and 1,4-addition to nitroolefins provide substituted 2-fluoro-3-(2-nitroethyl)pyridines. A facile oxidative Nef reaction/reductive amination/intramolecular SNAr sequence furnishes 7-azaindolines. Finally, optional regioselective electrophilic C5-substitution (e.g., bromination or nitration) and subsequent in situ oxidation delivers highly functionalized 7-azaindoles in high overall efficiency.
ABSTRACT
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.
Subject(s)
Pharmaceutical Preparations/chemical synthesis , Drug Design , Molecular Structure , Pharmaceutical Preparations/chemistryABSTRACT
1,3-Diols engage in ruthenium-catalyzed hydrogen transfer in the presence of alkyl hydrazines to provide 1,4-disubstituted pyrazoles. Regioselective synthesis of unsymmetrical pyrazoles from ß-hydroxy ketones is also described.
ABSTRACT
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.
Subject(s)
Pharmaceutical Preparations/chemical synthesis , Molecular Structure , Pharmaceutical Preparations/chemistryABSTRACT
New drugs are introduced to the market every year and each represents a privileged structure for its 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 26 NCEs that were launched in the world in 2011.