6-Substituted 1H-quinolin-2-ones and 2-methoxy-quinolines: Synthesis and evaluation as inhibitors of steroid 5α reductases types 1 and 2

Baston, Eckhard; Palusczak, Anja; Hartmann, Rolf W.

doi:10.1016/s0223-5234(00)01167-3

Cited by 54 publications

(32 citation statements)

References 21 publications

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“…Accordingly, introduction of substituents into the benzyloxy moiety might lead to further enhancement of selectivity. While this hypothesis was confirmed by the meta-methoxy (13), dimethoxy (16) and the chloro derivatives (17)(18)(19), the monomethoxy compounds (14)(15) showed different results. Compounds 14 (meta-methoxy, SF = 16) and 15 (para-methoxy, SF = 12) revealed similar selectivity toward 17b-HSD2 as the nonsubstituted benzyloxy compound 12 (SF = 13).…”

Section: Biologymentioning

confidence: 95%

“…An analogous concept has already been proved successful for the treatment of androgendependent diseases, such as benign prostatic hyperplasia and alopecia, by using 5a-reductase inhibitors. [16][17][18][19] Proof-of-concept for the treatment of breast cancer was performed in different mouse models. [20][21][22] However, no 17b-HSD1 inhibitor has reached clinical trials so far.…”

Section: Introductionmentioning

confidence: 99%

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Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety

et al. 2011

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An attractive target that has still to be explored for the treatment of estrogen-dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17β-HSD1 lowers intracellular E2 concentrations and thus presents a therapeutic target for estrogen-dependent pathologies. Recently, we reported a new class of highly active and selective 17β-HSD1 inhibitors: bicyclic substituted hydroxyphenylmethanones. Here, further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function. Twenty-nine novel inhibitors were synthesized and evaluated for 17β-HSD1 inhibition in a cell-free and cellular assay, for selectivity toward 17βHSD2 and estrogen receptors (ER) alpha and beta, as well as for metabolic stability. The best compound exhibited IC50 values of 12 nM (cell-free assay) and 78 nM (cellular assay), high selectivity for 17β-HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein-ligand interactions of this compound with 17β-HSD1.

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Section: Biologymentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety

et al. 2011

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“…Chemistry 1 H NMR spectra were recorded on a Bruker AM-400 (400 MHz) in CDCl 3 or DMSO-d 6 for compounds 21 -30 and B. Chemical shifts are reported as d values (ppm) relative to internal tetramethylsilane (d 0 ppm).…”

Section: Methodsmentioning

confidence: 99%

N -substituted 4-(4-carboxyphenoxy)benzamides. Synthesis and Evaluation as Inhibitors of Steroid-5α-reductase Type 1 and 2

Picard

Hartmann

2002

Journal of Enzyme Inhibition and Medicinal Chemistry

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In search of non-steroidal inhibitors of human prostatic 5alpha-reductase, we recently described N-substituted 4'-biphenyl-4-carboxylic acids. Here, we report the optimisation of this series of compounds by increasing the conformational flexibility using an ether linker between the steroidal A-C ring mimetics. Ten new compounds were synthesised and tested against human and rat isozymes 1 and 2. The substances showed a broad range of activity from 36% inhibition at a concentration of 10 microM to an IC50 value of 60 nM for compounds 22 and 29 respectively. The most potent compound 26 showed an IC50 value improved by a factor of 5 from 1.9 microM to 0.38 microM in comparison with the parent biphenyl compound 15.

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“…Similarly, pyridones 8 and 9 (n = 1,2; X = CON(i-Pr) 2 ; R 1 , R 2 = H,Me) where the B and C rings of the steroid system have been replaced by an acyclic linker display relatively weak activity versus both 5␣-R isozymes [54][55][56]. Removal of the C ring led to decrease of potency, too, although the appropriate substituent in 7 afforded a selective, but still weak 5␣R-1 inhibitor (Table 2) [57].…”

Section: Piperidones Quinolinones and Pyridonesmentioning

confidence: 99%

Selective non-steroidal inhibitors of 5α-reductase type 1

Occhiato

Guarna

Danza

et al. 2004

The Journal of Steroid Biochemistry and Molecular Biology

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6-Substituted 1H-quinolin-2-ones and 2-methoxy-quinolines: Synthesis and evaluation as inhibitors of steroid 5α reductases types 1 and 2

Cited by 54 publications

References 21 publications

Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety

Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety

N -substituted 4-(4-carboxyphenoxy)benzamides. Synthesis and Evaluation as Inhibitors of Steroid-5α-reductase Type 1 and 2

Selective non-steroidal inhibitors of 5α-reductase type 1

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