Abstract
In this review the preclinical medicinal chemistry, biochemistry and clinical results achieved in the treatment of prostatic disease with dutasteride, a dual inhibitor of type 1 and type 2 5α-reductase are described. During the discovery phase, dutasteride was optimized to inhibit both forms of human 5 α-reductase (5AR) via extensive structure activity relationship studies versus the cloned human isozymes. Dutasteride has subsequently been shown to improve disease measures in patients with symptomatic benign prostatic hyperplasia (BPH) in three randomized, placebo-controlled, Phase III clinical studies lasting for 2 years. Additionally, dutasteride is now under study for the ability to reduce the incidence of prostate cancer in men at high risk of the disease - an indication where the unique dual inhibitor nature, half-life and tolerability of dutasteride may be especially significant factors in determining treatment success. The connections between preclinical drug design and clinical outcomes during the discovery and development of dutasteride are exemplified.
Keywords: dihydrofinasteride-NADP adduct, 5AR isozymes, Vermeulen, progesterone, prostate cDNA library
Current Topics in Medicinal Chemistry
Title: Discovery and Clinical Development of Dutasteride, a Potent Dual 5α- Reductase Inhibitor
Volume: 6 Issue: 5
Author(s): Stephen V. Frye
Affiliation:
Keywords: dihydrofinasteride-NADP adduct, 5AR isozymes, Vermeulen, progesterone, prostate cDNA library
Abstract: In this review the preclinical medicinal chemistry, biochemistry and clinical results achieved in the treatment of prostatic disease with dutasteride, a dual inhibitor of type 1 and type 2 5α-reductase are described. During the discovery phase, dutasteride was optimized to inhibit both forms of human 5 α-reductase (5AR) via extensive structure activity relationship studies versus the cloned human isozymes. Dutasteride has subsequently been shown to improve disease measures in patients with symptomatic benign prostatic hyperplasia (BPH) in three randomized, placebo-controlled, Phase III clinical studies lasting for 2 years. Additionally, dutasteride is now under study for the ability to reduce the incidence of prostate cancer in men at high risk of the disease - an indication where the unique dual inhibitor nature, half-life and tolerability of dutasteride may be especially significant factors in determining treatment success. The connections between preclinical drug design and clinical outcomes during the discovery and development of dutasteride are exemplified.
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Cite this article as:
Frye V. Stephen, Discovery and Clinical Development of Dutasteride, a Potent Dual 5α- Reductase Inhibitor, Current Topics in Medicinal Chemistry 2006; 6 (5) . https://dx.doi.org/10.2174/156802606776743101
DOI https://dx.doi.org/10.2174/156802606776743101 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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