2. Academic Validation
  3. Discovery of 1'-(1-phenylcyclopropane-carbonyl)-3H-spiro[isobenzofuran-1,3'-pyrrolidin]-3-one as a novel steroid mimetic scaffold for the potent and tissue-specific inhibition of 11β-HSD1 using a scaffold-hopping approach

Discovery of 1'-(1-phenylcyclopropane-carbonyl)-3H-spiro[isobenzofuran-1,3'-pyrrolidin]-3-one as a novel steroid mimetic scaffold for the potent and tissue-specific inhibition of 11β-HSD1 using a scaffold-hopping approach

  • Bioorg Med Chem Lett. 2022 Aug 1;69:128782. doi: 10.1016/j.bmcl.2022.128782.
Colin Zhang 1,  Meizhong Xu 1,  Chunhong He 1,  Jincong Zhuo 1,  David M Burns 1,  Ding-Quan Qian 1,  Qiyan Lin 1,  Yun-Long Li 1,  Lihua Chen 1,  Eric Shi 1,  Costas Agrios 1,  Linkai Weng 1,  Vaqar Sharief 1,  Ravi Jalluri 1,  Yanlong Li 1,  Peggy Scherle 1,  Sharon Diamond 1,  Deborah Hunter 1,  Maryanne Covington 1,  Cindy Marando 1,  Richard Wynn 1,  Kamna Katiyar 1,  Nancy Contel 1,  Kris Vaddi 1,  Swamy Yeleswaram 1,  Gregory Hollis 1,  Reid Huber 1,  Steve Friedman 1,  Brian Metcalf 1,  Wenqing Yao 2
Affiliations

Affiliations

  • 1 Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.
  • 2 Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA. Electronic address: davidmmp2014@gmail.com.
PMID: 35537608 DOI: 10.1016/j.bmcl.2022.128782
Abstract

11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been identified as the primary Enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues resulting in the concomitant antagonism of Insulin action within these tissues. Dysregulation of 11β-HSD1, particularly in adipose tissues, has been associated with metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11β-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a three-point pharmacophore for 11β-HSD1 that was utilized to design a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of INCB13739. Clinical evaluation of INCB13739 confirmed for the first time that tissue-specific inhibition of 11β-HSD1 in patients with type 2 diabetes mellitus was efficacious in controlling glucose levels and reducing cardiovascular risk factors.

Keywords

11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitor; Metabolic syndrome; Spiro heterocyclic compounds; Steroid mimetic; Tissue specific; Type 2 diabetes mellitus.

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