71565-88-3Relevant articles and documents
Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor
Apgar, James M.,Wilkening, Robert R.,Parker, Dann L.,Meng, Dongfang,Wildonger, Kenneth J.,Sperbeck, Donald,Greenlee, Mark L.,Balkovec, James M.,Flattery, Amy M.,Abruzzo, George K.,Galgoci, Andrew M.,Giacobbe, Robert A.,Gill, Charles J.,Hsu, Ming-Jo,Liberator, Paul,Misura, Andrew S.,Motyl, Mary,Nielsen Kahn, Jennifer,Powles, Maryann,Racine, Fred,Dragovic, Jasminka,Fan, Weiming,Kirwan, Robin,Lee, Shu,Liu, Hao,Mamai, Ahmed,Nelson, Kingsley,Peel, Michael
, (2020/12/14)
We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.
Tetrahydropyridyloxadiazoles: Semirigid Muscarinic Ligands
Showell, Graham A.,Gibbons, Tracey L.,Kneen, Clare O.,MacLeod, Angus M.,Merchant, Kevin,et al.
, p. 1086 - 1094 (2007/10/02)
Recent studies have described novel azabicycle-based muscarinic agonists which readily penetrate into the central nervous system and are capable of displaying high efficacy at cortical sites.The current paper describes the synthesis and biochemical assesment of semirigid muscarinic ligands which were used to map the requirements of the cortical muscarinic receptor and to study the degree of conformational flexibility required to cause receptor activation.Analogues 6 and 9 provide high-efficacy muscarinic agonist at cortical sites; however, C-alkylation on the tetrahydropyridine ring resulted in more rigid analogues and showed lower predicted efficacy.Molecular mechanics calculations indicated a preference for the E rotameric form.This conformation was also observed in the X-ray crystal structure of ethenyloxadiazole 12.The new compounds were tested in biochemical assay designed to measure receptor affinity and to predict cortical efficacy.
Reactions of dimethylammonium Chloride with Methyl Ketones, Primary Amines, and Unsubstituted Amides
Gupton, John T.,Colon, Cesar,Harrison, Charles R.,Lizzi, Michael J.,Polk, Dale E.
, p. 4522 - 4524 (2007/10/02)
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