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International Journal of Molecular... Oct 2020Palmitoylethanolamide (PEA, -hexadecanoylethanolamide) is an endogenous compound belonging to the family of -acylethanolamines. PEA has anti-inflammatory and analgesic... (Review)
Review
Palmitoylethanolamide (PEA, -hexadecanoylethanolamide) is an endogenous compound belonging to the family of -acylethanolamines. PEA has anti-inflammatory and analgesic properties and is very well tolerated in humans. In the present article, the basal pharmacology of PEA is reviewed. In terms of its pharmacokinetic properties, most work has been undertaken upon designing formulations for its absorption and upon characterising the enzymes involved in its metabolism, but little is known about its bioavailability, tissue distribution, and excretion pathways. PEA exerts most of its biological effects in the body secondary to the activation of peroxisome proliferator-activated receptor-α (PPAR-α), but PPAR-α-independent pathways involving other receptors (Transient Receptor Potential Vanilloid 1 (TRPV1), GPR55) have also been identified. Given the potential clinical utility of PEA, not least for the treatment of pain where there is a clear need for new well-tolerated drugs, we conclude that the gaps in our knowledge, in particular those relating to the pharmacokinetic properties of the compound, need to be filled.
Topics: Amides; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Ethanolamines; Gene Expression Regulation; Humans; PPAR alpha; Palmitic Acids; Receptors, Cannabinoid; Tissue Distribution
PubMed: 33114698
DOI: 10.3390/ijms21217942 -
Cell Sep 2022We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral...
We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed 184 6-12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6-12 residue size range cross membranes with an apparent permeability greater than 1 × 10 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics.
Topics: Amides; Hydrogen; Hydrogen Bonding; Lipids; Peptides
PubMed: 36041435
DOI: 10.1016/j.cell.2022.07.019 -
Science (New York, N.Y.) Apr 2020The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug...
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (M, also called 3CL) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 M and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
Topics: Amides; Animals; Antiviral Agents; Betacoronavirus; Binding Sites; Cell Line, Tumor; Coronavirus 3C Proteases; Crystallography, X-Ray; Cysteine Endopeptidases; Drug Design; Half-Life; Humans; Lung; Mice; Models, Molecular; Protease Inhibitors; Protein Domains; Protein Multimerization; Pyridones; SARS-CoV-2; Viral Nonstructural Proteins; Virus Replication
PubMed: 32198291
DOI: 10.1126/science.abb3405 -
Chemical Reviews Oct 2021In this contribution, we provide a comprehensive overview of acyclic twisted amides, covering the literature since 1993 (the year of the first recognized report on... (Review)
Review
In this contribution, we provide a comprehensive overview of acyclic twisted amides, covering the literature since 1993 (the year of the first recognized report on acyclic twisted amides) through June 2020. The review focuses on classes of acyclic twisted amides and their key structural properties, such as amide bond twist and nitrogen pyramidalization, which are primarily responsible for disrupting to π* conjugation. Through discussing acyclic twisted amides in comparison with the classic bridged lactams and conformationally restricted cyclic fused amides, the reader is provided with an overview of amidic distortion that results in novel conformational features of acyclic amides that can be exploited in various fields of chemistry ranging from organic synthesis and polymers to biochemistry and structural chemistry and the current position of acyclic twisted amides in modern chemistry.
Topics: Amides; Chemistry Techniques, Synthetic; Lactams; Molecular Conformation; Nitrogen
PubMed: 34406005
DOI: 10.1021/acs.chemrev.1c00225 -
Nature Feb 2024Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics...
Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4 T cells and agonism of the pregnane X receptor. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.
Topics: Animals; Humans; Bifidobacterium; Bile Acids and Salts; CD4-Positive T-Lymphocytes; Clostridium; Cohort Studies; Crohn Disease; Enterococcus; Esters; Fatty Acids; Inflammatory Bowel Diseases; Metabolomics; Phenotype; Pregnane X Receptor; Reproducibility of Results; Tandem Mass Spectrometry; Amides
PubMed: 38052229
DOI: 10.1038/s41586-023-06906-8 -
Journal of the American Chemical Society Jan 2023Selective functional group interconversions in complex molecular settings underpin many of the challenges facing modern organic synthesis. Currently, a privileged subset...
Selective functional group interconversions in complex molecular settings underpin many of the challenges facing modern organic synthesis. Currently, a privileged subset of functional groups dominates this landscape, while others, despite their abundance, are sorely underdeveloped. Amines epitomize this dichotomy; they are abundant but otherwise intransigent toward direct interconversion. Here, we report an approach that enables the direct conversion of amines to bromides, chlorides, iodides, phosphates, thioethers, and alcohols, the heart of which is a deaminative carbon-centered radical formation process using an anomeric amide reagent. Experimental and computational mechanistic studies demonstrate that successful deaminative functionalization relies not only on outcompeting the H-atom transfer to the incipient radical but also on the generation of polarity-matched, productive chain-carrying radicals that continue to react efficiently. The overall implications of this technology for interconverting amine libraries were evaluated via high-throughput parallel synthesis and applied in the development of one-pot diversification protocols.
Topics: Catalysis; Amines; Amides; Bromides; Chlorides
PubMed: 36548788
DOI: 10.1021/jacs.2c11453 -
Angewandte Chemie (International Ed. in... Jul 2021Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means of bioinformatics and enzyme... (Review)
Review
Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means of bioinformatics and enzyme engineering opens up an immense variety of selective reactions. Biocatalysis especially provides excellent opportunities for late-stage modification often superior to conventional de novo synthesis. Enzymes have proven to be useful for direct introduction of functional groups into complex scaffolds, as well as for rapid diversification of compound libraries. Particularly important and highly topical are enzyme-catalysed oxyfunctionalisations, halogenations, methylations, reductions, and amide bond formations due to the high prevalence of these motifs in pharmaceuticals. This Review gives an overview of the strengths and limitations of enzymatic late-stage modifications using native and engineered enzymes in synthesis while focusing on important examples in drug development.
Topics: Amides; Biocatalysis; Enzymes
PubMed: 33453143
DOI: 10.1002/anie.202014931 -
NMR in Biomedicine Jun 2023Amide proton transfer (APT) imaging, a variant of chemical exchange saturation transfer MRI, has shown promise in detecting ischemic tissue acidosis following impaired... (Review)
Review
Amide proton transfer (APT) imaging, a variant of chemical exchange saturation transfer MRI, has shown promise in detecting ischemic tissue acidosis following impaired aerobic metabolism in animal models and in human stroke patients due to the sensitivity of the amide proton exchange rate to changes in pH within the physiological range. Recent studies have demonstrated the possibility of using APT-MRI to detect acidosis of the ischemic penumbra, enabling the assessment of stroke severity and risk of progression, monitoring of treatment progress, and prognostication of clinical outcome. This paper reviews current APT imaging methods actively used in ischemic stroke research and explores the clinical aspects of ischemic stroke and future applications for these methods.
Topics: Animals; Humans; Protons; Amides; Stroke; Magnetic Resonance Imaging; Ischemic Stroke; Acidosis
PubMed: 35322482
DOI: 10.1002/nbm.4734 -
Journal of Medicinal Chemistry Nov 2020The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the... (Review)
Review
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 properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, p, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.
Topics: Amides; Carbamates; Click Chemistry; Drug Design; Pyridines; Structure-Activity Relationship; Triazoles; Urea
PubMed: 32686940
DOI: 10.1021/acs.jmedchem.0c00530 -
Angewandte Chemie (International Ed. in... Aug 2022The asymmetric hydroaminocarbonylation of olefins represents a straightforward approach for the synthesis of enantioenriched amides, but is hampered by the necessity to...
The asymmetric hydroaminocarbonylation of olefins represents a straightforward approach for the synthesis of enantioenriched amides, but is hampered by the necessity to employ CO gas, often at elevated pressures. We herein describe, as an alternative, an enantioselective hydrocarbamoylation of alkenes leveraging dual copper hydride and palladium catalysis to enable the use of readily available carbamoyl chlorides as a practical carbamoylating reagent. The protocol is applicable to various types of olefins, including alkenyl arenes, terminal alkenes, and 1,1-disubstituted alkenes. Substrates containing a diverse range of functional groups as well as heterocyclic substructures undergo functionalization to provide α- and β-chiral amides in good yields and with excellent enantioselectivities.
Topics: Alkenes; Amides; Catalysis; Molecular Structure; Palladium; Stereoisomerism
PubMed: 35657208
DOI: 10.1002/anie.202206692