Sandbox 45673

Function

Finasteride, branded as Proscar or Propecia, is a synthetic 4-azasteroid compound that acts as a 5α-reductase inhibitor.^[1] The 5α-reductase enzyme is very important in the metabolism of many of the steroids produced by the body, in particular the conversion of testosterone to dihydrotestosterone (DHT).^[1] For this reason, Finasteride is used as a treatment for benign prostate hyperplasia (BPH), which is caused by an overproduction of DHT in the male prostate.^[2] Pattern hair loss, another condition in men caused by the build up of DHT, can also be treated with Finasteride.^[3] Finasteride's affinity for 5α-reductase approaches that of testosterone, and can bind to two of the three isoenzymes of 5α-reductase, types I and II.^[2]

Structure

To see what Finasteride looks like unbound, click this link: . Finasteride belongs to the subclass of steroids called azasteroids. All steroids contain a core structure called a gonane, a structure composed of 3 cyclohexane rings and 1 cyclopentane ring "fused" together.^[4] Although a gonane has 6 chirality centers, giving it 64 possible steroisomers, the majority of steroids contain the 5α-gonane stereoisomer. ^[5] 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.^[4] 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 with a tert-butyl group bonded to the nitrogen atom, has been added onto the carbon 17.

Fig. 1. Structure of Finasteride.

Mechanism

Finasteride is a 5-alpha reductase inhibitor. There are three isoforms of 5α-reductase, types I, II, and III. While the drug has a higher affinity for the type II enzyme, it also inhibits the function of the type I and no affinity for type III.^[6]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.^[7]

Fig. 2. Proposed mechanism of inhibition by Bull et. al. Image shows how the inhibition of 5alpha-reductase is achieved as Finasteride is used as a substrate to create an enolate intermediate, similar to the one made during the reduction of testosterone. However, the complex created does not allow for the proton transfer needed to complete the reduction of NADP-Dihydrofinasteride to Finasteride, because of the change in the carbanion position^[7]

Medical Uses

Finasteride is used to shrink an enlarged prostate, also known as benign prostatic hyperplasia (BPH), in adult men. ^[8] Since the male prostate is located near the bladder, enlargement places stress on the bladder and causes difficulty with passing urine. Common symptoms include, long period of time before urine flow, feeling the bladder is not empty, and dribbling urine.^[9] This medication works by blocking the enzyme 5α-reductase, which prevents conversion of testosterone to the natural body hormone, dihydrosestosterone (DHT) that causes growth of the prostate. As a result, reducing the amount of dihydrotestosterone causes the prostate to shrink and allows urine pass more easily.

Finasteride can also lead to improvements in Androgenetic alopecia, commonly called male pattern baldness (MPB). This condition is also caused by a build up of DHT in tissues, which in the case of MPB, is the scalp. The build up of DHT causes androgen-dependent miniaturization of scalp hair follicles. Testosterone is the primary androgen in the body, but to be maximally active in scalp hair follicles it must be converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase. Inhibition of the enzyme with Finasteride has shown to reduce both serum and scalp skin DHT levels in balding men. In some patients, hair regrowth can occur.^[10] Side effects from Finasteride include but are not limited to, decreased sexual ability and desire (Leyden, et al., 1999).