Mississauga, Canada
Mississauga, Canada

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Rudolph A.,Alphora Research | Alberico D.,Alphora Research | Jordan R.,Alphora Research | Pan M.,Alphora Research | And 2 more authors.
Tetrahedron Letters | Year: 2013

A new synthetic strategy towards the C27-C35 subunit of Eribulin (1) has been devised to include a protected 1,2-amino alcohol at C34-C35. Early introduction of the C35 amino group in the synthesis of 1 increases the efficiency of the route. This new approach can be accomplished on a multi-gram scale and allows for the successful synthesis of Eribulin. © 2013 Elsevier Ltd. All rights reserved.


Spickler C.,Boehringer Ingelheim | Spickler C.,Institute Of Recherche Clinique Of Montreal | Lippens J.,Boehringer Ingelheim | Laberge M.-K.,Boehringer Ingelheim | And 17 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

Human rhinovirus (HRV) is the predominant cause of the common cold, but more importantly, infection may have serious repercussions in asthmatics and chronic obstructive pulmonary disorder (COPD) patients. A cell-based antiviral screen against HRV was performed with a subset of our proprietary compound collection, and an aminothiazole series with pan-HRV species and enteroviral activity was identified. The series was found to act at the level of replication in the HRV infectious cycle. In vitro selection and sequencing of aminothiazole series-resistant HRV variants revealed a single-nucleotide mutation leading to the amino acid change I42V in the essential HRV 3A protein. This same mutation has been previously implicated in resistance to enviroxime, a former clinical-stage antipicornavirus agent. Enviroxime-like compounds have recently been shown to target the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ). A good correlation between PI4KIIIβ activity and HRV antiviral potency was found when analyzing the data over 80 compounds of the aminothiazole series, covering a 750-fold potency range. The mechanism of action through PI4KIIIβ inhibition was further demonstrated by small interfering RNA (siRNA) knockdown of PI4KB, which reduced HRV replication and also increased the potency of the PI4KIIIβ inhibitors. Inhibitors from two different structural classes with promising pharmacokinetic profiles and with very good selectivity for PI4KIIIβ were used to dissociate compound-related toxicity from target-related toxicity. Mortality was seen in all dosing groups of mice treated with either compound, therefore suggesting that short-term inhibition of PI4KIIIβ is deleterious. Copyright © 2013, American Society for Microbiology.

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