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Titolo:
Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity
Autore:
Chand, P; Kotian, PL; Dehghani, A; El-Kattan, Y; Lin, TH; Hutchison, TL; Babu, YS; Bantia, S; Elliott, AJ; Montgomery, JA;
Indirizzi:
BioCryst Pharmaceut Inc, Birmingham, AL 35244 USA BioCryst Pharmaceut IncBirmingham AL USA 35244 Birmingham, AL 35244 USA
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 25, volume: 44, anno: 2001,
pagine: 4379 - 4392
SICI:
0022-2623(200112)44:25<4379:SSDASS>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
INFLUENZA-VIRUS; SIALIC-ACID; NEURAMINIDASE; INHIBITORS; ANALOGS; REPLICATION; AMANTADINE; REDUCTION; MECHANISM; BINDING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Chand, P BioCryst Pharmaceut Inc, 2190 Pkwy Lake Dr, Birmingham, AL 35244 USA BioCryst Pharmaceut Inc 2190 Pkwy Lake Dr Birmingham AL USA 35244
Citazione:
P. Chand et al., "Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity", J MED CHEM, 44(25), 2001, pp. 4379-4392

Abstract

The design and synthesis of novel, orally active, potent, and selective inhibitors of influenza neuraminidase differing structurally from existing neuraminidase inhibitors are described. X-ray crystal structures of complexesof neuraminidase with known five- and six-membered ring inhibitors revealed that potent inhibition of the enzyme is determined by the relative positions of the interacting inhibitor substituents (carboxylate, glycerol, acetamido, hydroxyl) rather than by the absolute position of the central ring. This led us to design potential neuraminidase inhibitors in which the cyclopentane ring served as a scaffold for substituents (carboxylate, guanidino, acetamido, alkyl) that would interact with the four binding pockets of the neuraminidase active site at least as effectively as those of the established six-membered ring inhibitors such as DANA (2), zanamivir (3), and oseltamivir (4). A mixture of the isomers was prepared initially. Protein crystallography of inhibitor-enzyme complexes was used to screen mixtures of isomers in order to identify the most active stereoisomer. A synthetic route to the identified candidate 50 was developed, which featured (3 + 2) cycloaddition of 2-ethylbutyronitrile oxide to methyl (1S,4R)-4 [(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (43). Structures of the synthetic compounds were verified by NMR spectroscopy using nuclear Overhauser effect methodology. Two new neuraminidase inhibitors discovered in this work, 50 and54, have IC50 values vs neuraminidase from influenza A and B of <1 and < 10 nM, respectively. These IC50 values are comparable or superior to those for zanamivir and oseltamivir, agents recently approved by the FDA for treatment of influenza. The synthetic route used to prepare 50 and 54 was refined so that synthesis of pure active isomer 54, which has five chiral centers, required only seven steps from readily available intermediates. Further manipulation was required to prepare deoxy derivative 50. Because the activities of the two compounds are comparable and 54 [RWJ-270201 (BCX-1812)] is the easier to synthesize, it was selected for further clinical evaluation.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/09/20 alle ore 19:33:23