title: Discovery of camphor-derived pyrazolones as 11β-hydroxysteroid dehydrogenase type 1 inhibitors.
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.
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Gillespie
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Sherrie
authors.initials: S
authors.lastname: Pietranico-Cole
authors.affiliation: Metabolic and Vascular Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Myers
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Bilotta
authors.affiliation: Metabolic and Vascular Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Karin
authors.initials: K
authors.lastname: Conde-Knape
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Nader
authors.initials: N
authors.lastname: Fotouhi
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Goodnow
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Guertin
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hamilton
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Nancy-Ellen
authors.initials: NE
authors.lastname: Haynes
authors.affiliation: Drug Metabolism and Pharmacokinetics, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Baolian
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Lida
authors.initials: L
authors.lastname: Qi
authors.affiliation: Metabolic and Vascular Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Scott
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Sung-Sau
authors.initials: SS
authors.lastname: So
authors.affiliation: Metabolic and Vascular Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Spence
authors.affiliation: Metabolic and Vascular Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Taub
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Thakkar
authors.affiliation: Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Jefferson W
authors.initials: JW
authors.lastname: Tilley
authors.affiliation: Metabolic and Vascular Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Zwingelstein
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002164:Camphor / Q000737:chemistry*; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005260:Female; D006854:Hydrocortisone / Q000097:blood; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D047069:Pyrazolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D047069:Pyrazolones; D002164:Camphor; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone
keywords: 11βHSD1; Hit-to-lead; Pharmacodynamic model; Type 2 diabetes