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
The design and synthesis of novel, orally active, potent, and selective inh
ibitors of influenza neuraminidase differing structurally from existing neu
raminidase inhibitors are described. X-ray crystal structures of complexes
of neuraminidase with known five- and six-membered ring inhibitors revealed
that potent inhibition of the enzyme is determined by the relative positio
ns of the interacting inhibitor substituents (carboxylate, glycerol, acetam
ido, hydroxyl) rather than by the absolute position of the central ring. Th
is led us to design potential neuraminidase inhibitors in which the cyclope
ntane ring served as a scaffold for substituents (carboxylate, guanidino, a
cetamido, alkyl) that would interact with the four binding pockets of the n
euraminidase active site at least as effectively as those of the establishe
d six-membered ring inhibitors such as DANA (2), zanamivir (3), and oseltam
ivir (4). A mixture of the isomers was prepared initially. Protein crystall
ography of inhibitor-enzyme complexes was used to screen mixtures of isomer
s in order to identify the most active stereoisomer. A synthetic route to t
he identified candidate 50 was developed, which featured (3 + 2) cycloaddit
ion of 2-ethylbutyronitrile oxide to methyl (1S,4R)-4 [(tert-butoxycarbonyl
)amino]cyclopent-2-ene-1-carboxylate (43). Structures of the synthetic comp
ounds were verified by NMR spectroscopy using nuclear Overhauser effect met
hodology. Two new neuraminidase inhibitors discovered in this work, 50 and
54, 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 fo
r zanamivir and oseltamivir, agents recently approved by the FDA for treatm
ent 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 ma
nipulation was required to prepare deoxy derivative 50. Because the activit
ies of the two compounds are comparable and 54 [RWJ-270201 (BCX-1812)] is t
he easier to synthesize, it was selected for further clinical evaluation.