title: Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes.
abstract: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure-activity relationship of a series of piperazine sulfonamide-based 11β-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11β-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies.
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Zhao-Kui
authors.initials: ZK
authors.lastname: Wan
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Eva
authors.initials: E
authors.lastname: Chenail
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Huan-Qiu
authors.initials: HQ
authors.lastname: Li
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Manus
authors.initials: M
authors.lastname: Ipek
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Vipin
authors.initials: V
authors.lastname: Suri
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Seung
authors.initials: S
authors.lastname: Hahm
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Bard
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Kristine
authors.initials: K
authors.lastname: Svenson
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Xianbin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Xiangping
authors.initials: X
authors.lastname: Li
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Johnson
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Ariful
authors.initials: A
authors.lastname: Qadri
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Darrell
authors.initials: D
authors.lastname: Panza
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Mylene
authors.initials: M
authors.lastname: Perreault
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: James F
authors.initials: JF
authors.lastname: Tobin
authors.affiliation: Worldwide Research and Development, Pfizer Inc. , 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
authors.forename: Eddine
authors.initials: E
authors.lastname: Saiah
keywords: 11β-hydroxysteroid dehydrogenase type I (HSD1); diet-induced obesity; piperazine sufonamides; type II diabetes