The discovery of potent, selective, and orally bioavailable PDE9 inhibitors as potential hypoglycemic agents

Michael P Deninno; Melissa Andrews; Andrew S Bell; Yue Chen; Cynthia Eller-Zarbo; Nan Eshelby; John B Etienne; Dianna E Moore; Michael J Palmer; Michael S Visser; Li J Yu; William J Zavadoski; E Michael Gibbs

doi:10.1016/j.bmcl.2009.03.024

The discovery of potent, selective, and orally bioavailable PDE9 inhibitors as potential hypoglycemic agents

Bioorg Med Chem Lett. 2009 May 1;19(9):2537-41. doi: 10.1016/j.bmcl.2009.03.024. Epub 2009 Mar 13.

Authors

Michael P Deninno¹, Melissa Andrews, Andrew S Bell, Yue Chen, Cynthia Eller-Zarbo, Nan Eshelby, John B Etienne, Dianna E Moore, Michael J Palmer, Michael S Visser, Li J Yu, William J Zavadoski, E Michael Gibbs

Affiliation

¹ Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA.

PMID: 19339180
DOI: 10.1016/j.bmcl.2009.03.024

Abstract

Starting from a non-selective pyrazolo-pyrimidone lead, the sequential use of parallel medicinal chemistry and directed synthesis led to the discovery of potent, highly selective, and orally bioavailable PDE9 inhibitors. The availability of these tools allowed for a thorough evaluation of the therapeutic potential of PDE9 inhibition.

MeSH terms

3',5'-Cyclic-AMP Phosphodiesterases / chemistry*
3',5'-Cyclic-AMP Phosphodiesterases / metabolism
Administration, Oral
Catalytic Domain
Crystallography, X-Ray
Cyclic GMP / metabolism
Diabetes Mellitus / drug therapy
Drug Design
Humans
Hypoglycemia / drug therapy*
Hypoglycemic Agents / administration & dosage*
Hypoglycemic Agents / chemical synthesis*
Hypoglycemic Agents / pharmacology
Inhibitory Concentration 50
Models, Chemical
Permeability
Phosphodiesterase Inhibitors / chemical synthesis*
Phosphodiesterase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Hypoglycemic Agents
Phosphodiesterase Inhibitors
3',5'-Cyclic-AMP Phosphodiesterases
PDE9A protein, human
Cyclic GMP