Azasteroids: structure-activity relationships for inhibition of 5.alpha.-reductase and of androgen receptor binding

Abstract

A series of steroids, primarily 4-azasteroids, were prepared and tested in vitro as inhibitors of human and rat prostatic 5 alpha-reductase and of binding of dihydrotestosterone to the rat androgen receptor. The primary structural modifications were changes of the A ring and of moieties attached at the C-17 position of the steroid nucleus. New A-ring modifications included the 4-cyano-3-oxo-delta 4 system in the carbocyclic series and 1 alpha-CN, 1 alpha-CH3, 1 alpha,2 alpha-CH2, 2 beta-F, 2-aza, 2-oxa, and A-homo changes in the 3-oxo-4-aza series. In addition, 4-azasteroids with a D-homo ring or methyl substitution at C-7 (alpha and beta) or C-16 (alpha and beta) were prepared. The majority of the C-17 substituents were prepared from reactive intermediates derived from the 17 beta-COOH. Enhanced 5 alpha-reductase inhibition in both the human and rat enzyme assays is seen with 4-CN substitution on 3-oxo-delta 4 steroids and with a C-17 side chain incorporating a lipophilically substituted semipolar group on the 4-aza-3-oxo-5 alpha-androstane nucleus. Fewer highly active compounds were found in the human enzyme assay than in the rat assay. Structural requirements for inhibition of the rat androgen receptor are much different from those for inhibition of the enzyme. The 17 beta-OH moiety enhances potency more than any other feature while introduction of double bonds at C-1 or C-5 in the azasteroid gives a small improvement. Azasteroids unsubstituted at the 4-position show greatly diminished receptor activity.

Spectrophotometric Method for the Assay of Steroid 5α-Reductase Activity of Rat Liver and Prostate Microsomes

“…21 The IC50 value of finasteride to rat 5α-SR in prostate microsomes was also evaluated to be 11 nM by Häusler et al, 22 13 nM by Igarashi et al 23 and 237 nM by Mitamura et al 13 The reported IC50 values of fenasteride to rat 5α-SR in prostate homogenate were in the range from 6.8 to 147 nM. [24][25][26][27][28][29][30] The reason for such a difference may be related to differences in experimental conditions of enzyme activity evaluation such as pH, testosterone concentration and enzyme preparation.…”

Microbial Oxidation of Finasteride With Macrophomina Phaseolina(kucc 730)

“…Finasteride [17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-en-3-one] (1) is a potent inhibitor of 5α-reductase, an enzyme which catalyzes the conversion of testosterone into dihydrotestosterone in many organs [1]. Finasteride (1) is used in the treatment of hair loss [2], and benign prostate hyperplasia, both these disorders are associated with in-situ high levels of increased dihydrotestosterone.…”

“…It is also employed for the prevention of prostate cancer [3]. Previously, biotransformation of finasteride (1) has been reported by various fungi, including Selenastrum capricornutum [4], Mortierella isabellina, Cunninghamella elegans, and Bacillus megaterium [5].…”

An Efficient Synthesis of Dutasteride: Utilizing Benzoyl Group as Novel Lactamic Protecting Group

“…Dutasteride belongs to azasteriod class of compounds and function as a 5α-reductase inhibitor 1 which prevents the conversion of the androgen sex hormone testosterone into the more potent metabolite dihydrotestosterone (DHT). In 2009, South Korea has been licensed dutasteride for the treatment of androgenetic alopecia and in Japan 2015.…”