71565-88-3Relevant academic research and scientific papers
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.
Unexpected formation of acylformamidines by reaction of primary carboxamides with MeONa in DMF in the presence of CHCl3
Anelli, Pier Lucio,Brocchetta, Marino,Copez, Debora,Palano, Daniela,Visigalli, Massimo,Paoli, Paola
, p. 15827 - 15832 (2007/10/03)
Dichlorocarbene, which is generated by reaction of CHCl3 with MeONa, is likely to chlorinate DMF to produce tile Vilsmeier-Haack-Arnold salt that in the presence of excess MeONa, gives DMF dimethylacetal (2). This latter reacts with primary amides to yield the corresponding N,N-dimethyl-N'-acylformamidines. Solid state structure of N-[(dimethylamino)methylene]phenoxyacetamide (4) obtained by X-ray crystallography is also reported.
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.
Synthesis and muscarinic activities of 1,2,4-thiadiazoles
MacLeod,Baker,Freedman,Patel,Merchant,Roe,Saunders
, p. 2052 - 2059 (2007/10/02)
A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and 1-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hy
