Neuramidase inhibitors

M. Wei wer, C.-C. Chen, M. M. Kemp, and R. J. Linhardt, Synthesis and biological evaluation of non-hydrolyzable 1,2,3-triazole-linked sialic acid derivatives as neuramidase inhibitors, Eur. J. Org. Chem. (2009) 2611-2620. 

HIV fusion inhibitors, 3 151-152 HIV neuramidase inhibitors, target structure-based database searches, 6 14... 

The neuramidase inhibitor oseltamivir phosphate was discovered by Gilead Sciences and developed by Roche Pharmaceuticals under the name of Tamiflu (Scheme 5.13) to be used as an orally active antiviral compound for prevention and treatment of influenza infections. Because of the recent emergence of the avian flu, the demand for Tamiflu has gained momentum. Two industrially feasible syntheses are known, starting from (—)-shikimic acid and (—)-quinic acid, respectively (Scheme 5.13) [45]. 

Zaleplon (Sonata) [C IV] [Sedotive/Hypnotic] Uses Insomnia Action A nonbenzodiazepine sedative/hypnotic, a pyrazolopyrimidine Dose 5-20 mg hs PRN -1- w/ renal/hepatic insuff, elderly Caution [C, /-] w/ mental/ psychological conditions Contra Component allergy Disp Caps SE HA, edema, amnesia, somnolence, photosens Interactions t CNS depression W/ CNS d es-sants, imipramine, thioridazine, EtOH X effects W/ carbamazepine, phenobarbital, phenytoin, rifampin EMS Concurrent EtOH can t adverse CNS effects OD May cause profound CNS depression symptomatic and supportive Zanamivir (Relenza) [Antiviral/Neuramidase Inhibitor] Uses Influenza A (including HlNl swine flu) B Action X Viral neuraminidase Dose Adults Feds > 7 y.2 inhal (10 mg) bid for 5 d initiate w/in 48 h of Sxs Caution [C, M] Contra Pulm Dz Disp Powder for inhal SE Bron-chospasm, HA, GI upset EMS Does not reduce risk of transmitting virus monitor for bronchospasm or other severe resp events OD May cause resp problems s5rmptomatic and supportive... 

Y. Y. Yeung, S. Hong, and E. J. Corey, A short enantioselective pathway for the synthesis of the anti-influenza neuramidase inhibitor oseltamivir from 1,3-butadiene and acrylic acid, J. Am. Chem. Soc., 128 (2006) 6310-6311. 

Steindl, T., Langer, T. Influenza virus neuramidase inhibitors generation and comparison of structure -based and common feature pharmacophore hypotheses and their application in virtual screening. J. Chem. Inf. Comput. Sci. 2004, 44, 1849-1856. 

Ishikawa H, Suzuki T, Hayashi Y (2009) High-Yielding Synthesis of the Anti-influenza Neuramidase Inhibitor (-)-Oseltamivir by Three One-Pot Operations. Angew Chem Int Ed 48 1304... 

H. Ishikawa, T. Suzuki, Y. Hayashi, Angew. Chem. Int. Ed. 2009, 48, 1304—1307. High-yielding synthesis of the antiinfluenza neuramidase inhibitor (-)-oseltamivir by three one-pot operations. 

RWJ-270201), a neuramidase inhibitor used as an anti-influenza agent. ... 

One of the most appealing aspects of these multicomponent syntheses is the reactivity of the components. Often, the reaction sequence commences without the aid of external catalysts and still preserves selectivity. However, sometimes the reactive center is created in situ, which does require the assistance of an external catalyst. Transition metals, for instance, can be effectively used to induce reactivity, like in the synthesis of another viral protein inhibitor. The work of Garner and coworkers provided a new route to the core of a novel influenza neuramidase inhibitor in one pot [38]. The [C -I- NC -I- CC] coupling reaction proceeds via a metalated azomethine ylide by condensation of the amine 134 and aldehyde 132, which undergoes a [3 -l- 2] cycloaddition with activated dipolarophile 133 (Scheme 14.17). 

Garner, R, Weerasinghe, L., Youngs, W. J., Wright, B., Wilson, D., Jacobs, D. (2012). [C-I-NC-I-CC] coupling-enabled synthesis of influenza neuramidase inhibitor A-315675. Organic Letters, 14, 1326-1329. 

Corey and co-workers reported the stereoselective bromination of 61 in their total synthesis of the anti-influenza neuramidase inhibitor Tamiflu to occur in 95% yield and excellent stereoselectivity providing ( )-62. Here, Corey used the allyl bromide system as a precursor to a diene. 

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