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Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as inhibitors of 17α-hydroxylase-C17,20-lyase (Cyp17).
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Jul 15; Vol. 28 (13), pp. 2270-2274. Date of Electronic Publication: 2018 May 22. - Publication Year :
- 2018
-
Abstract
- The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation.<br /> (Copyright © 2018. Published by Elsevier Ltd.)
- Subjects :
- Animals
Cytochrome P-450 Enzyme Inhibitors chemical synthesis
Cytochrome P-450 Enzyme Inhibitors chemistry
Guinea Pigs
Half-Life
Microsomes, Liver metabolism
Piperazines chemical synthesis
Piperazines chemistry
Stereoisomerism
Stilbenes chemical synthesis
Stilbenes chemistry
Structure-Activity Relationship
Cytochrome P-450 Enzyme Inhibitors pharmacokinetics
Drug Design
Piperazines pharmacokinetics
Steroid 17-alpha-Hydroxylase antagonists & inhibitors
Stilbenes pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 28
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 29803730
- Full Text :
- https://doi.org/10.1016/j.bmcl.2018.05.040