Discovery of camphor-derived pyrazolones as 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Paul Gillespie; Sherrie Pietranico-Cole; Michael Myers; Joseph A Bilotta; Karin Conde-Knape; Nader Fotouhi; Robert A Goodnow Jr; Kevin R Guertin; Matthew M Hamilton; Nancy-Ellen Haynes; Baolian Liu; Lida Qi; Yonglin Ren; Nathan R Scott; Sung-Sau So; Cheryl Spence; Rebecca Taub; Kshitij Thakkar; Jefferson W Tilley; Catherine Zwingelstein

doi:10.1016/j.bmcl.2014.04.049

Discovery of camphor-derived pyrazolones as 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Bioorg Med Chem Lett. 2014 Jun 15;24(12):2707-11. doi: 10.1016/j.bmcl.2014.04.049. Epub 2014 Apr 21.

Authors

Paul Gillespie¹, Sherrie Pietranico-Cole², Michael Myers³, Joseph A Bilotta², Karin Conde-Knape³, Nader Fotouhi², Robert A Goodnow Jr², Kevin R Guertin², Matthew M Hamilton², Nancy-Ellen Haynes², Baolian Liu⁴, Lida Qi², Yonglin Ren³, Nathan R Scott², Sung-Sau So², Cheryl Spence³, Rebecca Taub³, Kshitij Thakkar², Jefferson W Tilley², Catherine Zwingelstein³

Affiliations

¹ Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States. Electronic address: paul.gillespie@roche.com.
² Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
³ Metabolic and Vascular Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
⁴ Drug Metabolism and Pharmacokinetics, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.

PMID: 24815509
DOI: 10.1016/j.bmcl.2014.04.049

Abstract

Starting from screening hit, (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7), we optimized the potency and pharmacokinetic properties. This led to the identification of compounds with good in vivo activity in a mouse pharmacodynamic model of inhibition of 11βHSD1.

Keywords: 11βHSD1; Hit-to-lead; Pharmacodynamic model; Type 2 diabetes.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Animals
Camphor / chemistry*
Drug Discovery*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Female
Hydrocortisone / blood
Inhibitory Concentration 50
Mice
Molecular Structure
Pyrazolones / chemical synthesis*
Pyrazolones / pharmacology*
Rats

Substances

Enzyme Inhibitors
Pyrazolones
Camphor
11-beta-Hydroxysteroid Dehydrogenase Type 1
Hydrocortisone