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Journal of Medicinal Chemistry
Scopus
ISSN 0022-2623 · American Chemical Society · 28 artikel di indeks
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Chirality of New Drug Approvals (2013–2022): Trends and Perspectives
Many drugs are chiral with their chirality determining their biological interactions, safety, and efficacy. Since the 1980s, there has been a regulatory preference to bring single enantiomer to market. This perspective discusses trends related to chirality that have developed in the past decade…
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Macrocycles in Drug Discovery─Learning from the Past for the Future
We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs are mainly used in infectious disease and oncology, while oncology is the major indication for the clinical candidates and in the…
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“Magic Chloro”: Profound Effects of the Chlorine Atom in Drug Discovery
Chlorine is one of the most common atoms present in small-molecule drugs beyond carbon, hydrogen, nitrogen, and oxygen. There are currently more than 250 FDA-approved chlorine-containing drugs, yet the beneficial effect of the chloro substituent has not yet been reviewed. The seemingly simple…
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Rings in Clinical Trials and Drugs: Present and Future
We present a comprehensive analysis of all ring systems (both heterocyclic and nonheterocyclic) in clinical trial compounds and FDA-approved drugs. We show 67% of small molecules in clinical trials comprise only ring systems found in marketed drugs, which mirrors previously published findings for…
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Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19
High Resolution Image Download MS PowerPoint Slide The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19…
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Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis
The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the past 40 years. As a result, kinase inhibitors are today one of the most important classes of drugs. The FDA approved 73…
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Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor
High Resolution Image Download MS PowerPoint Slide KRAS G12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRAS G12C, selective inhibition of KRAS G12D presents a significant challenge due to the requirement of…
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Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design
The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st…
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Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras
A current bottleneck in the development of proteolysis targeting chimeras (PROTACs) is the empirical nature of linker length structure–activity relationships (SARs). A multidisciplinary approach to alleviate the bottleneck is detailed here. First, we examine four published synthetic approaches that…
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COVID-19: Drug Targets and Potential Treatments
Currently, humans are immersed in a pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which threatens public health worldwide. To date, no drug or vaccine has been approved to treat the severe disease caused by this coronavirus, COVID-19. In this paper…
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Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon
A quaternary carbon bears four other carbon substituents or combination of four non-hydrogen substituents at four vertices of a tetrahedron. The spirocyclic quaternary carbon positioned at the center of a bioactive molecule offers conformational rigidity, which in turn reduces the penalty for…
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On the Promise of Photopharmacology Using Photoswitches: A Medicinal Chemist’s Perspective
Photopharmacology is a growing area of endeavor that employs photoswitchable ligands to allow for light-dependent pharmacological activity. By coupling light to therapeutic action, improved spatial and temporal selectivity can be achieved and subsequently harnessed for new concepts in therapy…
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Reactive Oxygen Species (ROS)-Responsive Prodrugs, Probes, and Theranostic Prodrugs: Applications in the ROS-Related Diseases
Elevated levels of reactive oxygen species (ROS) have commonly been implicated in a variety of diseases, including cancer, inflammation, and neurodegenerative diseases. In light of significant differences in ROS levels between the nonpathogenic and pathological tissues, an increasing number of…
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Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry
Sulfoximines have been largely disregarded in medicinal chemistry for a long time. However, recently, they have risen to the apparent level of stardom on the drug discovery scene. Considering the outstanding properties of sulfoximines, this versatile functional group has advanced to implementation…
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Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight
It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic…
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Spirocyclic Scaffolds in Medicinal Chemistry
Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compounds has given rise to the development of synthetic methodologies for the preparation of spirocyclic scaffolds. In this Perspective, we summarize the diverse…
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Identification of the Clinical Development Candidate MRTX849 , a Covalent KRASG12C Inhibitor for the Treatment of Cancer
Abstract Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target’s resurgence. As previously reported, the tetrahydropyridopyrimidines were…
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Amide Bond Bioisosteres: Strategies, Synthesis, and Successes
Abstract The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic…
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Metabolic and Pharmaceutical Aspects of Fluorinated Compounds
The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochemical properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated molecules are…
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α‑Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment
Abstract The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these…