The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors

Renee Aspiotis; Denis Deschênes; Daniel Dubé; Yves Girard; Zheng Huang; France Laliberté; Susana Liu; Robert Papp; Donald W Nicholson; Robert N Young

doi:10.1016/j.bmcl.2010.07.076

The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors

Bioorg Med Chem Lett. 2010 Sep 15;20(18):5502-5. doi: 10.1016/j.bmcl.2010.07.076. Epub 2010 Jul 21.

Authors

Renee Aspiotis¹, Denis Deschênes, Daniel Dubé, Yves Girard, Zheng Huang, France Laliberté, Susana Liu, Robert Papp, Donald W Nicholson, Robert N Young

Affiliation

¹ Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Hwy, Kirkland, Québec., Canada H9H 3L1. renee_aspiotis@merck.com

PMID: 20709547
DOI: 10.1016/j.bmcl.2010.07.076

Abstract

The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50=0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized.

MeSH terms

Animals
Asthma / drug therapy
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
Humans
Inhibitory Concentration 50
Male
Phosphodiesterase Inhibitors / chemical synthesis
Phosphodiesterase Inhibitors / chemistry*
Phosphodiesterase Inhibitors / pharmacokinetics
Phosphodiesterase Inhibitors / pharmacology*
Quinolines / chemical synthesis
Quinolines / chemistry*
Quinolines / pharmacokinetics
Quinolines / pharmacology*
Rats
Rats, Wistar
Structure-Activity Relationship

Substances

Phosphodiesterase Inhibitors
Quinolines
Cyclic Nucleotide Phosphodiesterases, Type 4