Finasteride (PropeciaŽ)
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Cynthia L. Schieck, Graduate Student Department of Medicinal Chemistry Medical College of Virginia Campus, Virginia Commonwealth University [Molecule of the Month - August 1998] Would you like to go from this A drug for male pattern baldness has recently been approved for use by the FDA.[1] It is called finasteride and is being sold under the name Propecia for baldness in men. This article describes the synthesis of finasteride, how it works, SAR for this class of compounds, and application to another medical condition, benign prostatic hyperplasia. FINASTERIDE: A MEDICINAL CHEMISTRY PERSPECTIVE CHEMISTRY
MECHANISM OF ACTION
Due to the potential importance of 5-α-reductase inhibition in a variety of disease states,
pharmaceutical companies have published many studies concerning its
structure-activity relationships (SARs). Figure 3 shows the basic
SAR for 4-azasteroids at 5-α-reductase
(published in a review by Kenny et al.[3]).
In general, a ketone in the 3-position is preferred. Lipophilic
substituents in the 17-position are thought to bind in a lipophilic pocket
of the receptor. Small lipophilic groups are tolerated around the ring as
well as expanding the A-ring from six to seven-membered. The size and
shape of the amide substituents at C-17 may influence both selectivity
between types I and II and potency at both isoforms. Other structural
classes of molecules are known to bind to 5α-R including 10 and 6-azasteroids, benzoquinolinones,
benzoylaminophenoxybutanoic acid derivatives, and polyunsaturated fatty
acids.[6-9]
Detailed SAR for these and other structural types are available and can be
found in the literature.
MEDICINAL EFFECTS BENIGN PROSTATIC HYPERPLASIA (BPH)
The former has been targeted through the use of α-1 adrenergic antagonists and will not be discussed here. The latter is the objective of 5a-R inhibition. Published information pertaining to the cause of BPH and related disorders has been available for some time.[3] In 1895, males, who had BPH, were castrated and showed a decrease in prostate size and improved BPH symptoms. In 1944, it was noted that males (<40 years of age) without testicular function had a reduced tendency to develop bph and prostate cancer. these observations pointed to testosterone as influencing bph and possibly prostate cancer. in the prostate, however, testosterone is rapidly converted to dihydrotestosterone (dht) by the action of 5-α-reductase. DHT has a 4-5 fold higher affinity for androgen receptors than testosterone and comprises ~90% of the total androgen content. Plus, it was noted that male pseudohermaphrodites (individuals deficient in 5-α-reductase) did not develop BPH. These two pieces of evidence implicated DHT as playing a role in the development of BPH. Decreased levels of DHT might decrease prostate size which would, in turn, improve the symptoms of BPH. . . thus, the development of finasteride, a 5-α-reductase inhibitor. So far, results have shown that men with the most severe BPH symptoms respond best to finasteride treatment (5mg/day). The New England Journal of Medicine reported that, under this regimen, prostate volume decreased by 19% and urinary flow increased by 22-23%.[10] The treatment is reported to have no effect on sperm count, motility, or morphology. Loss of libido and/or impotence was reported by a small percentage of the patients. The alternative therapy for BPH being surgery, finasteride could prove useful and invaluable for a number of BPH- symptomatic men. MALE PATTERN BALDNESS (ANDROGENETIC ALOPECIA) Referring again to observations made throughout history:
These observations point to the influence of male androgens on scalp hair growth and the importance of DHT.[13,14] As mentioned above, finasteride has recently been approved for use in the treatment of male pattern baldness and will be available soon.[11,12] Finasteride has the potential for application in a variety of medical disorders. Its action on the male hormonal system gives it selectivity without unnecessary side effects. Benign prostatic hyperplasia (BPH) and male pattern baldness have been approved for use. Acne, female hirsutism, and prostate cancer could be potential applications of finasteride. While the drug has been found to be safe, it is not without fault. It should be noted that finasteride decreases the level of prostate specific antigen (PSA), an indicator of prostate cancer. Masking PSA levels could decrease our ability to monitor this type of cancer. Also, due to the possibility of harming male fetuses, women of reproductive age are cautioned against the drug.[15] Future publications will examine applications and safety issues associated with this versatile drug and its place in current medicinal chemistry.
Figure 4. An overlay of molecular models of finasteride (purple) and testosterone (yellow). Date posted: 02/03/98 REFERENCES1. Literature on the approval of finasteride in the
treatment of male pattern baldness can be found on the web: http://www.abcnews.com/sections/living/baldpill1222/index.html 2. Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N.
G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.;
Brooks, J. R.; Berman, C. Azasteroids: Structure-Activity Relationships
for Inhibition of 5-α-Reductase and of
Androgen Receptor Binding. J. Med. Chem. 1986, 29,
2298-2315. 3. Kenny, B.; Ballard, S.; Blagg, J.; Fox, D.
Pharmacological Options in the Treatment of Benign Prostatic Hyperplasia.
J. Med. Chem. 1997, 40, 1293-1315. 4. Bull, H. G. Mechanism-Based Inhibition of Human
Steroid 5-α-Reductase by Finasteride:
Enzyme-Catalyzed Formation of NADP-Dihydrofinasteride, a Potent
Bisubstrate Analog Inhibitor. J. Am. Chem. Soc. 1996,
118, 2359-2365. 5. Moss, M. L.; Kuzmic, P.; Stuart, J. D.; Tian, G.;
Peranteau, A. G.; Frye, S. V.; Kadwell, S. H.; Kost, T. A.; Overton, L.
K.; Patel, I. R. Inhibition of Human Steroid 5-α Reductases type I and II by 6-Aza-Steroids: Structural
Determinants of One-Step vs. Two-Step Mechanism. Biochemistry
1996, 35, 3457-3464. 6. Guarna, A.; Belle, C.; Machetti, F.; Occhiato, E.
G.; Payne, A. H.; Cassiani, C.; Comerci, A.; Danza, G.; De Bellis, A.;
Dini, S.; Marrucci, A.; Serio, M. 19-Nor-10-azasteroids: A Novel Class of
Inhibitors for Human Steroid 5-α-Reductases 1 and 2. J. Med. Chem. 1997,
40, 1112-1129. 7. Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Hiner,
R. N.; Dorsey, G. F.; Noe, R. A.; Unwalla, R. J.; Batchelor, K. W.;
Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; van Arnold, J.; Bickett,
D. M.; Moss, M. L.; Tian, G.; Lee, F. W.; Tippin, T. K.; James, M. K.;
Grizzle, M. K.; Long, J. E.; Croom, D. K. Structure-Activity Relationships
for Inhibition of Type 1 and 2 Human 5-α-Reductase and Human Adrenal 3-α-Hydroxy-β-steroid
Dehydrogenase/3-Keto-β-steroid Isomerase
by 6-Azaandrost-4-en-3-ones: Optimization of the C17 Substituent. J.
Med. Chem. 1995, 38, 2621-2627. 8. Chen, W.; Zouboulis, C. C.; Orfanos, C. E. The
5-α-Reductase System and Its Inhibitors.
Dermatology 1996, 193, 177-184. 9. Li, X.; Chen, C.; Singh, S. M.; Labire, F. The
Enzyme and Inhibitors of 4-Ene-3-oxosteroid 5-α-Oxidoreductase. Steroids 1995, 60,
430-441. 10. Rittmaster, R. S. Finasteride. NEJM
1994, 330, 120-125. 11. Please see http://www.regrowth.com/reference/treatments/future/propecia.htm. 12. Please see http://www.pslgroup.com/dg/4ec06.htm. 13. Dallob, A. L.; Sadick, N. S.; Unger, W.; Lipert,
S.; Geissler, L. A.; Gregoire, S. L.; Hguyen, H. H.; Moore, E. C.; Tanaka,
W. K. The Effect of Finasteride, a 5-α-Reductase Inhibitor, on Scalp Skin Testosterone and
Dihydrotestosterone Concentrations in Patients with Male Pattern Baldness.
J. Clin. Endocrin. Metabol. 1994, 79,
703-706. 14. Walsh, D. S.; Dunn, C. L.; James, W. D.
Improvement in Androgenetic Alopecia (Stage V) Using Topical Minoxidil in
a Retinoid Vehicle and Oral Finasteride. Arch. Dermatol.
1995, 131, 1373-1375. 15. Sudduth, S. L.; Koronkowski, M. J. Finasteride:
The First 5-α-Reductase Inhibitor.
Pharmacotherapy 1993, 13,309-329. |
Web page originally on VCU website. Written and last updated Aug 1998.
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