Sialidase inhibitors cyclopentane derivatives

A number of researchers have reported and demonstrated that maintaining the appropriate position of the substituents on a cyclic scaffold to interact with the established conserved amino acid residues involved in substrate binding can lead to development of new classes of influenza virus sialidase inhibitors [117]. Two drugs based on five-membered ring scaffolds have been developed as potent sialidase inhibitors. Cyclopentane derivative 24 (BCX-1812, peramivir) [117, 118] and pyrrolidine derivative 25 (ABT-675) [119] show nanomolar levels of inhibition of both influenza A and B viral sialidases (Fig. 17.13). 

Chan T-H, Xin Y-C, von Itzstein M (1997) Synthesis of phosphonic add analogs of siaUc acids (Neu5Ac and KDN) as potential sialidase inhibitors. J Org Chem 62 3500-3504 Chand P, Kotian PL, Dehghani A, El-Kattan Y, Lin T-H, Hutchison TL, Babu YS, Bantia S, Elliott AJ, Montgomery JA (2001) Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity. J Med Chem 44 4379 392... 

Compounds featuring this typical functionalized cyclopentane unit are the platelet aggregation inhibitor compound (1) of AstraZeneca, the HCV NS3 NS4A protease inhibitor (2) claimed by Tibotec for the treatment of Hepatitis C, and a Neuraminidase (Sialidase) inhibitor (3) discovered by Biocryst for the treatment of influenza (Figure 4.6). Likewise, the widely used nucleoside analog reverse transcriptase inhibitor Abacavir (4), administered against HIV, produced by GlaxoSmithKline, as well as Medivir s beta-secretase 1 (BACE 1) inhibitor (5) for the treatment of Alzheimer s dementia can be probably derived from this hydroformylation protocol. 

Compounds derived from a cyclopentane or pyrrolidine skeleton have recently been attracting close attention as next-generation neuraminidase inhibitors [121,122,123,124,125], and active efforts have been made for screening of such compounds (O Scheme 18). Attempts have also been made to prevent virus infection by removing the tracheal sialic acid receptors (the starting point of viral infection) through direct inhalation of sialidase [126]. 

---