Irreversible inhibition of human 5.alpha.-reductase

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai

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514172, 514176, 514177, 514253, 514284, 435 25, 544 77, 544 78, 536 2624, A01N 4500

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059624426

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BRIEF SUMMARY
SUMMARY OF THE INVENTION

The invention concerns the treatment of hyperandrogenic conditions in humans by the formation of a novel mechanism-based irreversible inhibitor of human 5.alpha.-reductase enzymes from 3-oxo-4-azasteroids having a 1,2-double bond and the pyridine-nucleotide cofactor of the 5.alpha.-reductase enzyme, NADPH. The invention further relates to the isolated inhibitor-cofactor complex.


BACKGROUND OF THE INVENTION

Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system. Androgenic alopecia is also known as androgenetic alopecia. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethyl-isobutyranilide. See Neri, et al., Endocrinol. 1972, 91 (2). However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
The principal mediator of androgenic activity in some target organs, e.g. the prostate, is 5.alpha.-dihydrotestosterone ("DHT"), formed locally in the target organ by the action of testosterone-5.alpha.-reductase. Inhibitors of testosterone-5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs.
The enzyme 5.alpha.-reductase catalyzes the reduction of testosterone to the more potent androgen, dihydrotestosterone, as shown below: ##STR1##
Finasteride, (17.beta.-(N-tert-butylcarbamoyl)-3-oxo-4-aza-5.alpha.-androst-1-ene-3-one ) as shown below, is a potent inhibitor of the human prostate enzyme. ##STR2## Under the trade name PROSCAR.RTM., finasteride is known to be useful in the treatment of hyperandrogenic conditions; see eg. U.S. Pat. No. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition afflicting to some degree the majority of men over age 55. Finasteride's utility in the treatment of androgenic alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published Oct. 5, 1988; EP 0 285,383, published Oct. 5, 1988; Canadian Patent no. 1,302,277; and Canadian Patent no. 1,302,276.
There are two isozymes of 5.alpha.-reductase in humans. One isozyme (type 1) predominates in sebaceous glands of facial and skin tissue and is relatively insensitive to finasteride; the other (type 2) predominates in the prostate and is potently inhibited by finasteride.
In clinical trials, the efficacy of finasteride far exceeded expectations based on its perceived potency against the human prostate enzyme, for which finasteride was first thought to be a simple, rapidly-reversible inhibitor with K.sub.i =26 nM. For instance, circulating concentrations of finasteride comparable to this Ki actually reduced levels of dihydrotestosterone to values approaching those found in individuals genetically deficient in the prostate isozyme, and as long as two weeks were required for dihydrotestosterone to return to basal levels after withdrawal of finasteride (Stoner, J. Steroid. Biochem. Molec. Biol. 37: 375-378 (1990) and Gormley et al., J. Clin. Endocrinol. Metabol. 70: 1136-1141 (1990)). A closer evaluation of the interaction of finasteride with the human prostate (type 2) isozyme led to appreciation that finasteride and certain analogs thereof are slow-binding inhibitors, such that t

REFERENCES:
patent: 5098908 (1992-03-01), Steinberg et al.
patent: 5120742 (1992-06-01), Rasmusson et al.
patent: 5151429 (1992-09-01), Rasmusson et al.
patent: 5656613 (1997-08-01), Bull et al.
Mellin et al., J. Steroid Biochem. Mol. Biol., vol. 44, No. 2 pp. 121-131, (1993). (CAPLUS Abstract).

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