Discovery and clinical development of dutasteride, a potent dual 5alpha-reductase inhibitor.
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 2,5alpha-reductase are described. During the discovery phase, dutasteride was optimized to inhibit both forms of human 5 alpha-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.
Frye
Stephen V
SV
Department of High Throughput Chemistry, Discovery Research, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA. Stephen.v.frye@gsk.com
D000818:Animals; D001378:Azasteroids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors*; D017326:Clinical Trials, Phase III as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001378:Azasteroids; D004791:Enzyme Inhibitors; D042944:Cholestenone 5 alpha-Reductase; D000068538:Dutasteride