Effect of lipophilicity modulation on inhibition of human rhinovirus capsid binders

Andrew Morley; Nicholas Tomkinson; Andrew Cook; Catherine MacDonald; Richard Weaver; Sarah King; Lesley Jenkinson; John Unitt; Christopher McCrae; Tim Phillips

doi:10.1016/j.bmcl.2011.08.083

Effect of lipophilicity modulation on inhibition of human rhinovirus capsid binders

Bioorg Med Chem Lett. 2011 Oct 15;21(20):6031-5. doi: 10.1016/j.bmcl.2011.08.083. Epub 2011 Aug 24.

Authors

Andrew Morley¹, Nicholas Tomkinson, Andrew Cook, Catherine MacDonald, Richard Weaver, Sarah King, Lesley Jenkinson, John Unitt, Christopher McCrae, Tim Phillips

Affiliation

¹ Department of Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, UK. andy.morley@astrazeneca.com

PMID: 21907579
DOI: 10.1016/j.bmcl.2011.08.083

Abstract

To try and generate broad spectrum human rhinovirus VP1 inhibitors with more attractive physicochemical, DMPK and safety profiles, we explored the current SAR of known VP1 compounds. This lead to the identification of specific structural regions where reduction in polarity can be achieved, so guiding chemistry to analogues with significantly superior profiles to previously reported inhibitors.

MeSH terms

Animals
Antiviral Agents / chemistry*
Antiviral Agents / metabolism
Antiviral Agents / pharmacology*
Capsid / drug effects*
Capsid Proteins / metabolism*
Humans
Microsomes / metabolism
Picornaviridae Infections / drug therapy*
Protein Binding
Pyridazines / chemistry
Pyridazines / metabolism
Pyridazines / pharmacology
Rats
Rats, Sprague-Dawley
Rhinovirus / drug effects*
Structure-Activity Relationship

Substances

Antiviral Agents
Capsid Proteins
Pyridazines