Nonsteroidal progesterone receptor ligands (I): Synthesis and SAR of new tetrahydronaphthofuranone derivatives

Tetrahydronaphthofuranones, based on the fungal metabolite PF1092C, was synthesized and evaluated for progesterone receptor (PR) binding affinities. Compounds 8b and 19i exhibited high affinity and acted as selective PR antagonists. We have synthesized a series of nonsteroidal progesterone receptor...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2006-07, Vol.14 (14), p.4850-4861
Main Authors: Shinei, Rie, Kurihara, Ken-ichi, Tanabe, Kiyoshi, Tabata, Yuji, Kurata, Yasushi, Hoshiko, Shigeru, Okonogi, Tsuneo
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cell Line
Furans - chemical synthesis
Furans - chemistry
Furans - pharmacology
Hormone Antagonists - chemical synthesis
Hormone Antagonists - chemistry
Hormone Antagonists - pharmacology
Hormones. Endocrine system
Humans
In Vitro Techniques
Kinetics
Ligands
Medical sciences
Naphthols - chemical synthesis
Naphthols - chemistry
Naphthols - pharmacology
Nonsteroidal progesterone receptor ligands
PF1092
Pharmacology. Drug treatments
PR antagonist
Receptors, Progesterone - agonists
Receptors, Progesterone - antagonists & inhibitors
Receptors, Progesterone - metabolism
Sesquiterpenes - chemical synthesis
Sesquiterpenes - chemistry
Sesquiterpenes - pharmacology
Structure-Activity Relationship
Tetrahydronaphthalenes - chemical synthesis
Tetrahydronaphthalenes - chemistry
Tetrahydronaphthalenes - pharmacology
Tetrahydronaphthofuranone
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Summary:Tetrahydronaphthofuranones, based on the fungal metabolite PF1092C, was synthesized and evaluated for progesterone receptor (PR) binding affinities. Compounds 8b and 19i exhibited high affinity and acted as selective PR antagonists. We have synthesized a series of nonsteroidal progesterone receptor (PR) ligands, tetrahydronaphthofuranones, structurally based on the fungal metabolite PF1092C. Structure–activity relationship studies revealed that substituents at the 6- and 7-positions were critical for PR binding affinity and for agonist or antagonist activity. Compounds in this series, exemplified by 19i, exhibited high affinity and high specificity for PR over other steroid hormone receptors and acted as selective PR antagonists. Further modification of PF1092C may generate compounds of potential pharmacological interest.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2006.03.018