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.

11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism Diabetes Mellitus, Type 2 / drug therapy Enzyme Inhibitors / pharmacology Humans Hydrocortisone / metabolism Metabolic Syndrome / metabolism
11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitor Metabolic syndrome Spiro heterocyclic compounds Steroid mimetic Tissue specific Type 2 diabetes mellitus

Journal

Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377

Informations de publication

Date de publication:
01 08 2022
Historique:
received: 09 03 2022
revised: 19 04 2022
accepted: 02 05 2022
pubmed: 11 5 2022
medline: 31 5 2022
entrez: 10 5 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.bmcl.2022.128782 PMID: 35537608
pubmed: 35537608
pii: S0960-894X(22)00258-X
doi: 10.1016/j.bmcl.2022.128782
pii:
doi:

Substances chimiques

Enzyme Inhibitors 0
11-beta-Hydroxysteroid Dehydrogenase Type 1 EC 1.1.1.146
Hydrocortisone WI4X0X7BPJ

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

128782

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Auteurs

Colin Zhang (C)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Meizhong Xu (M)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Chunhong He (C)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Jincong Zhuo (J)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

David M Burns (DM)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Ding-Quan Qian (DQ)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Qiyan Lin (Q)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Yun-Long Li (YL)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Lihua Chen (L)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Eric Shi (E)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Costas Agrios (C)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Linkai Weng (L)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Vaqar Sharief (V)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Ravi Jalluri (R)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Yanlong Li (Y)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Peggy Scherle (P)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Sharon Diamond (S)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Deborah Hunter (D)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Maryanne Covington (M)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Cindy Marando (C)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Richard Wynn (R)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Kamna Katiyar (K)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Nancy Contel (N)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Kris Vaddi (K)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Swamy Yeleswaram (S)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Gregory Hollis (G)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Reid Huber (R)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Steve Friedman (S)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Brian Metcalf (B)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA.

Wenqing Yao (W)

Incyte Research Institute, 1801 Augustine Cut-off, Wilmington, DE 19880, USA. Electronic address: davidmmp2014@gmail.com.

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Alcohol oxidoreductases › NAD (+) and NADP (+) dependent Alcohol oxidoreductases › 11-beta-Hydroxysteroid dehydrogenases › 11-beta-Hydroxysteroid dehydrogenase type 1 › Discovery of...
questionsmedicales.fr › Maladies endocriniennes › Diabète › Diabète de type 2 › Discovery of...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Discovery of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Discovery of...
questionsmedicales.fr › Hormones corticosurrénaliennes › Hydroxycorticostéroïdes › 17-Hydroxycorticostéroïdes › Hydrocortisone › Discovery of...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Syndrome métabolique X › Discovery of...