Finasteride development

Among the candidates considered for development in this series was the t-Bu amide which was subsequently given the name finasteride and became the active ingredient in both PROSCAR and PROPECiA (Figure 3.2). Section 3.1 will tell the story of the development of a manufacturing process for finasteride. As in most programs at Merck, dmg candidates showing potential for improved performance over the lead compound were approved for development as the lead... 

Early process development and modification of the Medicinal Chemistry synthesis for the first kilogram-scale delivery of finasteride... 

When second generation candidates differing from finasteride only at the C17 position were considered for development, a second team was tasked with defining the synthesis while the first delivery of finasteride was being completed. Three ketones were considered as potential back-up compounds, the s-Bu, i-Pr, and i-Bu ketones (2,19, 3 in Scheme 3.4). Ideally, the new route would allow divergence at a late stage of the synthesis to make both finasteride and the ketone selected for... 

Our Chemical Engineering colleagues had developed an elegant impinging jet crystallization which provided excellent particle size control for the finasteride process [13]. In the final pilot plant campaign just before the factory start-up, the crystallization suddenly started producing a different particle size distribution and lower recovery. The problem was traced to a new finasteride solvate which reduced the solubility in the crystallization solvent system. Fortunately, only relatively... 

Finasteride has been clinically proved to reduce the median volume of the prostate in patients and is currently prescribed for the treatment of BPH. The compound also has demonstrated efficacy in the treatment of male pattern baldness and is prescribed for this indication as well. Subsequent to the discovery of finasteride, it was found that there are two isoforms of steroid 5a-reductase in mammals, type 1 and type 2. The type 2 isoform is primarily active in reproductive tissue, while the type 1 isoform contributes to DHT formation in the skin, liver, and reproductive tissue. Finasteride inhibits both isozymes in rats, but selectively inhibits the type 2 isozyme only in humans. It is hypothesized that dual inhibition of both isoforms of steroid 5a-reductase might prove more effective in treating BPH. Hence the GlaxoSmithKline group identified and developed dutasteride (Figure 8.18C). Dutasteride inactivates both human isoforms of steroid 5a-reductase by a mechanism similar to that described for finasteride (Bramson et al., 1997 see also the Web site www.avodart.com). Both finasteride and dutasteride have demonstrated clinical efficacy and are currently used in the treatment of BPH. 

The critical period for the induction of hypospadias by finasteride in rats is Days 16 to 17 of gestation (Clark et al., 1990a). It is unlikely that other agents would have a much earlier critical period since testosterone synthesis, which is required for the development of the penile urethra, begins in the rat on Day 15 of gestation (Habert and Picon, 1984). Thus, if treatment in the embryo-fetal development study... 

There are no data to support the use of finasteride in women with androgenic alopecia. Pregnant women should not be exposed to finasteride either by use or by handling crushed tablets because of the risk of hypospadias developing in a male fetus. 

Males with deficiency of the 5a-reductase isoenzyme do not develop acne, male pattern baldness, or enlarged prostates.274 The last fact was some of the impetus for development of the steroid 5a-reductase inhibitor finasteride, which is widely used to treat benign prostate enlargement 274/277/278 It is an enzyme-activated inhibitor in which the NADH reduces the C= C bond in the A ring, which is not in the same position as in the substrate. The resulting anion cannot become protonated but instead adds to the NAD+ as shown in Eq. 22-15. 

A 43-year-old man developed impaired vision in both eyes over 3 months. Anterior subcapsular opacities were found in both eyes, necessitating cataract extraction. He had been taking finasteride 1 mg/day for 3 years to treat the early stage of androgenic alopecia. It was suspected that the drug was responsible and the treatment was therefore withdrawn. 

A 23-year-old man who was taking finasteride 1 mg/ day for 2 months for androgenetic alopecia developed painful enlargement of his right breast (71). Treatment was withdrawn and resolution occurred after 2 months. 

Striking evidence of the association of finasteride with male breast cancer comes from the Medical Therapy of Prostatic Symptoms (MTOPS) study, a National Institutes of Health (NIH)-sponsored study of about 3047 men that compared finasteride, doxazosin, and the combination for the treatment of benign prostatic hyperplasia. The rate of breast cancer in this trial for men taking finasteride either alone or with doxazosin was four in 1554, or nearly 200 times that of the general population one man in the finasteride + doxazosin group and three in the finasteride-alone group developed male breast cancer (74). 

A 53-year-old man developed unilateral gynecomastia following finasteride therapy for alopecia (75). On needle biopsy the mammary mass was diagnosed as... 

A 30-year man who was being successfully treated for obesity with sibutramine started to take finasteride to treat alopecia. Soon afterwards he developed paranoid psychotic behavior. The reaction abated and disappeared when finasteride was withdrawn. 

Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development of prostate cancer. New Engl J Med 2003 349 215-24. 

Finasteride was developed as the first orally active, specific inhibitor of 5a-reductase for clinical use. Clinical studies in men with BPH demonstrated that treatment with finasteride reduced prostate size, improved urinary symptoms, and reduced the risk of developing serious BPH-related outcomes, including acute urinary retention (AUR) and the need for surgery, confirming the effects of DHT on the prostate. Additional studies also demonstrated that finasteride is an effective treatment in men with AGA. Several small studies have also suggested it is moderately efficacious in women with hirsutism. A number of other inhibitors of 5a-reductase are also presently in development for the treatment of BPH and AGA. 

In view of the fact that DHT had been implicated in AGA and in light of the potential advancement in the treatment of this disorder that could be provided by a safe oral pharmacologic therapy, finasteride was developed for the treatment of men with AGA. 

The development of the new class of compounds known as 5a-reduc-tase inhibitors has significantly advanced our understanding of androgen biology. Finasteride, a selective inhibitor of the human type 2 5a-reductase enzyme, was the first of this class of compounds in clinical development, and extensive clinical trials have established its usefulness... 

Development difficulties. Propecia (finasteride) is a synthetic steroid that functions as a competitive and specific inhibitor of 5a-reductase, the enzyme responsible for the synthesis of dihydrotestosterone from testosterone. 

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