Sandbox 45673: Difference between revisions
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==Structure== | ==Structure== | ||
To see what Finasteride looks like unbound, click this link: <scene name='74/745970/Finasteride_unbound/1'>FIT</scene>. Finasteride belongs to the subclass of steroids called azasteroids. All steroids contain a core structure called gonane, a structure composed of 3 cyclohexane rings and 1 cyclopentane ring "fused" together. Although gonane has 6 chirality centers, giving it 64 possible steroisomers, the majority of steroids contain the 5α-gonane stereoisomer. The function and naming of steroids are determined by what functional groups are attached to the rings of gonane and by the substitution of carbon atoms in the rings with different atoms. In the case of Finasteride, two methyl groups have been attached to carbons 10 and 13 of the gonane structure, placing it in the androstane classification of steroids. The gonane ring is further modified by the addition of a double bond at carbon 1 and a ketone to carbon 3. Carbon 4 in Finasteride has been substituted with a nitrogen atom, making Finasteride a 4-azasteroid. Finally, a carboxamide has been added onto the carbon 17. The nitrogen present in the carboxamide has been with a tert-butyl group. | To see what Finasteride looks like unbound, click this link: <scene name='74/745970/Finasteride_unbound/1'>FIT</scene>. Finasteride belongs to the subclass of steroids called azasteroids. All steroids contain a core structure called gonane, a structure composed of 3 cyclohexane rings and 1 cyclopentane ring "fused" together <ref name="10"> Lednicer D (2011). Steroid Chemistry at a Glance. Hoboken: Wiley. ISBN 978-0-470-66084-3 </ref>. Although gonane has 6 chirality centers, giving it 64 possible steroisomers, the majority of steroids contain the 5α-gonane stereoisomer. The function and naming of steroids are determined by what functional groups are attached to the rings of gonane and by the substitution of carbon atoms in the rings with different atoms. In the case of Finasteride, two methyl groups have been attached to carbons 10 and 13 of the gonane structure, placing it in the androstane classification of steroids. The gonane ring is further modified by the addition of a double bond at carbon 1 and a ketone to carbon 3. Carbon 4 in Finasteride has been substituted with a nitrogen atom, making Finasteride a 4-azasteroid. Finally, a carboxamide has been added onto the carbon 17. The nitrogen present in the carboxamide has been with a tert-butyl group. | ||
==Mechanism== | ==Mechanism== | ||
Finasteride is a 5-alpha reductase inhibitor. There are | Finasteride is a 5-alpha reductase inhibitor. There are three isoforms of the 5alpha-reductase enzyme, type I and II, and while the drug has a higher affinity for the type II enzyme, it also inhibits the function of the type I.<ref name="four"> Schieck, Cynthia L.(1998, August) "Finasteride (Propecia ®)". http://www.chm.bris.ac.uk/motm/finasteride/Finasteride%20(Propecia)%20-%20Feature%20Molecule.htm </ref> | ||
Typically 5α-redcutase turns testosterone into Dihydrotestosterone(DHT), but the enzyme will accept Finasteride as an alternate substrate; turning it into dihydrofinasteride through an enzyme bound, NADP-dihydrofinasteride adduct. Finasteride is similar in structure to testosterone and 5alpha-reductase has almost the same affinity for both molecules. However, Finasteride , having a high affinity for 5α-reductase, covalently binds to the enzyme as a Michael acceptor, through a functionally irreversible reaction. However, the NADP-dihydrofinasteride complex breaks down with a half life of about 1 month at 37˚C., which is why patients must continue taking the drug.<ref name="five"> Bull, Herbert G.*Garcia-Calvo,Margarita Andersson,Stefan†, Baginsky, Walter F.,Chan,H. Karen,Ellsworth,‡ Dina E., Miller,§ Randall R., Stearns,Ralph A.,Bakshi,Raman K.,Rasmusson, Gary H.,Tolman,Richard L., Myers,Robert W.,Kozarich,John W.,Harris,Georgianna S. (1995, August 6) Mechanism-Based Inhibition of Human Steroid 5R-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP-Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor. http://pubs.acs.org/doi/pdf/10.1021/ja953069t</ref> | Typically 5α-redcutase turns testosterone into Dihydrotestosterone(DHT), but the enzyme will accept Finasteride as an alternate substrate; turning it into dihydrofinasteride through an enzyme bound, NADP-dihydrofinasteride adduct. Finasteride is similar in structure to testosterone and 5alpha-reductase has almost the same affinity for both molecules. However, Finasteride , having a high affinity for 5α-reductase, covalently binds to the enzyme as a Michael acceptor, through a functionally irreversible reaction. However, the NADP-dihydrofinasteride complex breaks down with a half life of about 1 month at 37˚C., which is why patients must continue taking the drug.<ref name="five"> Bull, Herbert G.*Garcia-Calvo,Margarita Andersson,Stefan†, Baginsky, Walter F.,Chan,H. Karen,Ellsworth,‡ Dina E., Miller,§ Randall R., Stearns,Ralph A.,Bakshi,Raman K.,Rasmusson, Gary H.,Tolman,Richard L., Myers,Robert W.,Kozarich,John W.,Harris,Georgianna S. (1995, August 6) Mechanism-Based Inhibition of Human Steroid 5R-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP-Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor. http://pubs.acs.org/doi/pdf/10.1021/ja953069t</ref> | ||