Synthesis of B-NOR-4-AZA-5α-androstane compound as 5α-reductase inhibitor

Bioorganic & Medicinal Chemistry Letters
1994.0

Abstract

B-Nor-4-aza-5a-androstane derivative 1 was synthesized. The compound 1 showed potent inhibition activity against testosterone 5a-reductase.Testosterone 5a-reductase plays an important role in the pathology of benign prostatic hypertrophy. It converts testosterone in the prostate to 5a-dihydrotestosterone, whose accumulation is known to cause hypertrophy of the prostate.A series of 4-aza-steroid compounds have already been synthesized, and they were found to have 5a-reductase inhibition activity. Among them, N-(1,1-dimethylethyl)-3-oxo-4-aza-5a-androst-1-ene-17b-carboxamide, MK-906, was recently launched as a drug for benign prostatic hypertrophy. These compounds have a nitrogen at the C-4 position and a backbone structure similar to that of testosterone. In relation to the structure-activity relationship we were interested in modifying the backbone structure, in particular the B-ring. Namely, we focused attention on synthesizing a B-nor-4-aza-5a-androstane derivative. The conformation of B-nor-4-aza-5a-androstane, having a five-membered B ring, is not much different from that of 4-aza-5a-androstane based on molecular model inspection. In addition, we have already disclosed that the 4-aza-androstane derivative 2, having a 17b-benzhydrylcarbamoyl moiety, has highly potent inhibition activity against testosterone 5a-reductase. Therefore, the B-nor-4-aza-5a-androstane derivative 1 with a benzhydrylcarbamoyl moiety at the C-17 position was selected as a target compound. In this report we describe a synthesis of 1 and its 5a-reductase inhibition activity.

Knowledge Graph

Similar Paper

Synthesis of B-NOR-4-AZA-5α-androstane compound as 5α-reductase inhibitor
Bioorganic & Medicinal Chemistry Letters 1994.0
19-Nor-10-azasteroids:  A Novel Class of Inhibitors for Human Steroid 5α-Reductases 1 and 2
Journal of Medicinal Chemistry 1997.0
Activity of steroid 4 and derivatives 4a–4f as inhibitors of the enzyme 5α-reductase 1
Bioorganic & Medicinal Chemistry 2018.0
Azasteroids: structure-activity relationships for inhibition of 5.alpha.-reductase and of androgen receptor binding
Journal of Medicinal Chemistry 1986.0
Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors
Bioorganic & Medicinal Chemistry 2016.0
6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and 2 Human 5.alpha.-Reductase and Human Adrenal 3.beta.-Hydroxy-.DELTA.5-steroid Dehydrogenase/3-Keto-.DELTA.5-steroid Isomerase
Journal of Medicinal Chemistry 1994.0
Synthesis and biological evaluation of novel unsaturated carboxysteroids as human 5α-reductase inhibitors: A legitimate approach
European Journal of Medicinal Chemistry 2012.0
Synthesis and in Vitro Activity of 17.beta.-(N-Alkyl/arylformamido and N-alkyl/arylalkyl/arylamido)-4-methyl-4-aza-3-oxo-5.alpha.-androstan-3-ones as Inhibitors of Human 5.alpha.-Reductases and Antagonists of the Androgen Receptor
Journal of Medicinal Chemistry 1995.0
4,7.beta.-Dimethyl-4-azacholestan-3-one (MK-386) and Related 4-Azasteroids as Selective Inhibitors of Human Type 1 5.alpha.-Reductase
Journal of Medicinal Chemistry 1994.0
4-Aza-3-oxo-5.alpha.-androst-1-ene-17.beta.-N-arylcarboxamides as Dual Inhibitors of Human Type 1 and Type 2 Steroid 5.alpha.-Reductases. Dramatic Effect of N-Aryl Substituents on Type 1 and Type 2 5.alpha.-Reductase Inhibitory Potency
Journal of Medicinal Chemistry 1995.0