|
Inhibition of recombinant rat adrenal 3-beta-hydroxy-delta-5-steroid dehydrogenase
|
None
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : 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 by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent.
Year : 1995
Volume : 38
Issue : 14
First Page : 2621
Last Page : 2627
Authors : Frye SV, Haffner CD, Maloney PR, Hiner RN, Dorsey GF, Noe RA, Unwalla RJ, Batchelor KW, Bramson HN, Stuart JD.
Abstract : A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.
|
Inhibition of recombinant human 5-alpha reductase-1 at a concentration of 5 microL after pre-incubation for 10 minutes
|
None
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : 6-Azasteroids: potent dual inhibitors of human type 1 and 2 steroid 5 alpha-reductase.
Year : 1993
Volume : 36
Issue : 26
First Page : 4313
Last Page : 4315
Authors : Frye SV, Haffner CD, Maloney PR, Mook RA, Dorsey GF, Hiner RN, Batchelor KW, Bramson HN, Stuart JD, Schweiker SL.
|
Inhibition of recombinant human 5-alpha reductase-2 at a concentration of 5 microL after pre-incubation for 10 minutes
|
None
|
0.18
nM
|
|
Journal : J. Med. Chem.
Title : 6-Azasteroids: potent dual inhibitors of human type 1 and 2 steroid 5 alpha-reductase.
Year : 1993
Volume : 36
Issue : 26
First Page : 4313
Last Page : 4315
Authors : Frye SV, Haffner CD, Maloney PR, Mook RA, Dorsey GF, Hiner RN, Batchelor KW, Bramson HN, Stuart JD, Schweiker SL.
|
Binding affinity for human 5-alpha reductase 2 isozyme
|
Homo sapiens
|
0.18
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacological options in the treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 9
First Page : 1293
Last Page : 1315
Authors : Kenny B, Ballard S, Blagg J, Fox D.
|
Inhibition of type 2 steroid-5-alpha-reductase
|
None
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : 4,7 beta-Dimethyl-4-azacholestan-3-one (MK-386) and related 4-azasteroids as selective inhibitors of human type 1 5 alpha-reductase.
Year : 1994
Volume : 37
Issue : 23
First Page : 3871
Last Page : 3874
Authors : Bakshi RK, Patel GF, Rasmusson GH, Baginsky WF, Cimis G, Ellsworth K, Chang B, Bull H, Tolman RL, Harris GS.
|
In vitro inhibitory activity against human type 2 5-alpha reductase
|
None
|
0.18
nM
|
|
Journal : J. Med. Chem.
Title : 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.
Year : 1994
Volume : 37
Issue : 15
First Page : 2352
Last Page : 2360
Authors : Frye SV, Haffner CD, Maloney PR, Mook RA, Dorsey GF, Hiner RN, Cribbs CM, Wheeler TN, Ray JA, Andrews RC.
Abstract : 6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.
|
Inhibitory activity against 5-alpha Reductase-2 on human prostate homogenates from surgically derived benign hyperplastic tissue
|
Homo sapiens
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : 19-nor-10-azasteroids: a novel class of inhibitors for human steroid 5alpha-reductases 1 and 2.
Year : 1997
Volume : 40
Issue : 7
First Page : 1112
Last Page : 1129
Authors : Guarna A, Belle C, Machetti F, Occhiato EG, Payne AH, Cassiani C, Comerci A, Danza G, De Bellis A, Dini S, Marrucci A, Serio M.
Abstract : Steroid 5alpha-reductase is a system of two isozymes (5alphaR-1 and 5alphaR-2) which catalyzes the NADPH-dependent reduction of testosterone to dihydrotestosterone in many androgen sensitive tissues and which is related to several human endocrine diseases such as benign prostatic hyperplasia (BPH), prostatic cancer, acne, alopecia, pattern baldness in men and hirsutism in women. The discovery of new potent and selective 5alphaR inhibitors is thus of great interest for pharmaceutical treatment of these diseases. The synthesis of a novel class of inhibitors for human 5alphaR-1 and 5alphaR-2, having the 19-nor-10-azasteroid skeleton, is described. The inhibitory potency of the 19-nor-10-azasteroids was determined in homogenates of human hypertrophic prostates toward 5alphaR-2 and in DU-145 human prostatic adenocarcinoma cells toward 5alphaR-1, in comparison with finasteride (IC50 = 3 nM for 5alphaR-2 and approximately 42 nM for 5alphaR-1), a drug which is currently used for BPH treatment. The inhibition potency was dependent on the type of substituent at position 17 and on the presence and position of the unsaturation in the A and C rings. delta9(11)-19-Nor-10-azaandrost-4-ene-3,17-dione (or 10-azaestra-4,9(11)-diene-3,17-dione) (4a) and 19-nor-10-azaandrost-4-ene-3,17-dione (5) were weak inhibitors of 5alphaR-2 (IC50 = 4.6 and 4.4 microM, respectively) but more potent inhibitors of 5alphaR-1 (IC50 = 263 and 299 nM, respectively), whereas 19-nor-10-aza-5alpha-androstane-3,17-dione (7) was inactive for both the isoenzymes. The best result was achieved with the 9:1 mixture of delta9(11)- and delta8(9)-17beta-(N-tert-butylcarbamoyl)-19-nor-10-aza-4- androsten-3-one (10a,b) which was a good inhibitor of 5alphaR-1 and 5alphaR-2 (IC50 = 127 and 122 nM, respectively), with a potency very close to that of finasteride. The results of ab initio calculations suggest that the inhibition potency of 19-nor-10-azasteroids could be directly related to the nucleophilicity of the carbonyl group in the 3-position.
|
Inhibitory activity against type-1 human steroid 5-alpha-reductase.
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A comparison of steroidal and non-steroidal inhibitors of human steroid 5-reductase: New tricyclic aryl acid inhibitors of the type-1 isozyme
Year : 1996
Volume : 6
Issue : 4
First Page : 481
Last Page : 484
Authors : Abell AD, Brandt M, Levy MA, Holt DA
|
Inhibitory activity against type-2 human steroid 5-alpha-reductase.
|
None
|
4.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A comparison of steroidal and non-steroidal inhibitors of human steroid 5-reductase: New tricyclic aryl acid inhibitors of the type-1 isozyme
Year : 1996
Volume : 6
Issue : 4
First Page : 481
Last Page : 484
Authors : Abell AD, Brandt M, Levy MA, Holt DA
|
Inhibition of human steroid 5-alpha-reductase
|
Homo sapiens
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 17-azolyl steroids, potent inhibitors of human cytochrome 17 alpha-hydroxylase-C17,20-lyase (P450(17) alpha): potential agents for the treatment of prostate cancer.
Year : 1998
Volume : 41
Issue : 6
First Page : 902
Last Page : 912
Authors : Njar VC, Kato K, Nnane IP, Grigoryev DN, Long BJ, Brodie AM.
Abstract : A new synthetic route to a variety of novel delta 16-17-azolyl steroids is described: it involves the nucleophilic vinylic "addition-elimination" substitution reaction of 3 beta-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and azolyl nucleophiles. Some of these novel delta 16-17-azolyl steroids, 6, 17, 19, and 27-29, prepared in good overall yields, are very potent inhibitors of human and rat testicular P450(17) alpha. They are shown to be noncompetitive and appear to be slow-binding inhibitors of human P450(17) alpha. The most potent compounds are 3 beta-hydroxy-17-(1H-imidazol-1-yl)androsta-5,16-diene (17), 3 beta-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,-16-diene (19), and 17-(1H-imidazol-1-yl)androsta-4,16-dien-3-one (28), with Ki values of 1.2, 1.4, and 1.9 nM, respectively, being 20-32 times more potent than ketoconazole (Ki = 38 nM). Spectroscopic studies with a modified form of human P450(17) alpha indicate that the inhibition process involves binding of steroidal azole nitrogen to the heme iron of the enzyme. Furthermore, some of these potent P450(17) alpha inhibitors (27-29) are also powerful inhibitors of steroid 5 alpha-reductase, and others (17 and 19) appear to exhibit strong antiandrogenic activity in cultures of the LNCaP human prostatic cancer cell line. These novel compounds with impressive dual biological activities make them strong candidates for development as therapeutic agents for treatment of prostate cancer and other disease states which depend on androgens.
|
In vitro inhibitory activity against rat prostatic steroid 5-alpha-reductase
|
None
|
6.8
nM
|
|
Journal : J. Med. Chem.
Title : Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding.
Year : 1986
Volume : 29
Issue : 11
First Page : 2298
Last Page : 2315
Authors : Rasmusson GH, Reynolds GF, Steinberg NG, Walton E, Patel GF, Liang T, Cascieri MA, Cheung AH, Brooks JR, Berman C.
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.
|
Inhibition of rat Steroid 5-alpha-reductase was determined
|
None
|
28.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of B-NOR-4-AZA-5-androstane compound as 5-reductase inhibitor
Year : 1994
Volume : 4
Issue : 5
First Page : 729
Last Page : 732
Authors : Ishibashi K, Kurata H, Kojima K, Horikoshi H
|
Ability to inhibit Steroid 5-alpha-reductase in rat using Enzyme kinetics method.
|
None
|
54.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A practical synthesis of 3-substituted delta 3,5(6)-steroids as new potential 5 alpha-reductase inhibitor.
Year : 1998
Volume : 8
Issue : 15
First Page : 1949
Last Page : 1952
Authors : Tian W, Zhu Z, Liao Q, Wu Y.
Abstract : A new and practical synthetic approach to 3-substituted delta 3,5(6)-Steroids, as potential 5 alpha-reductase inhibitor, is described. The key step involves Pd-catalyzed coupling reaction of steroid 3-enol 5H-3-oxo-octafluoropentanosulfonates. 3-Phenylacetylenyl substituted delta 3,5(6)-steroid 3g and 3-phosphate substituted delta 3,5(6)-steroid 3f in our synthesized compounds exhibited high 5 alpha-reductase inhibitory activity in vitro assay.
|
Ability to inhibit Steroid 5-alpha-reductase in rat using Isotope method [3H]T to [3H]-DHT]
|
None
|
88.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A practical synthesis of 3-substituted delta 3,5(6)-steroids as new potential 5 alpha-reductase inhibitor.
Year : 1998
Volume : 8
Issue : 15
First Page : 1949
Last Page : 1952
Authors : Tian W, Zhu Z, Liao Q, Wu Y.
Abstract : A new and practical synthetic approach to 3-substituted delta 3,5(6)-Steroids, as potential 5 alpha-reductase inhibitor, is described. The key step involves Pd-catalyzed coupling reaction of steroid 3-enol 5H-3-oxo-octafluoropentanosulfonates. 3-Phenylacetylenyl substituted delta 3,5(6)-steroid 3g and 3-phosphate substituted delta 3,5(6)-steroid 3f in our synthesized compounds exhibited high 5 alpha-reductase inhibitory activity in vitro assay.
|
In vitro inhibitory activity against Steroid 5-alpha-reductase by using enzymic kinetics method
|
None
|
54.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 4-trifluoromethylsteroids: A novel class of steroid 5-reductase inhibitors
Year : 1997
Volume : 7
Issue : 24
First Page : 3113
Last Page : 3118
Authors : Xiang-Shu Fei, Wei-Sheng Tian, Qing-Yun Chen
|
In vitro inhibitory activity against Steroid 5-alpha-reductase by using isotope method
|
None
|
88.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 4-trifluoromethylsteroids: A novel class of steroid 5-reductase inhibitors
Year : 1997
Volume : 7
Issue : 24
First Page : 3113
Last Page : 3118
Authors : Xiang-Shu Fei, Wei-Sheng Tian, Qing-Yun Chen
|
In vitro inhibition of human steroid 5-alpha-reductase type 2 in SW-13-transfected cells
|
None
|
4.53
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro activity of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/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.
Year : 1995
Volume : 38
Issue : 7
First Page : 1158
Last Page : 1173
Authors : Li X, Singh SM, Labrie F.
Abstract : A number of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-3-oxo-4-aza-5 alpha-steroids were prepared from 17 beta-hydroxy-4-azasteroids and evaluated as inhibitors of human 5 alpha-reductase and antagonists of the androgen receptor. Jones' oxidation of 17 beta-hydroxy compounds gave the 17-keto-4-azasteroids, which were treated with amines and NaBH(OAc)3/NaBH3CN to give 17 beta-(N-alkyl/arylamino)-4-azasteroids 10-27. Alternatively, the above-indicated compounds were prepared from amines and 17-keto-4-azasteroids to form imines, which were then reduced with NaBH4. Formylation of amines 10-27 gave 17 beta-(N-alkylformamides) 28-41; however, acylation afforded 17 beta-[(N-alkyl/aryl)alkyl/arylamides] 42-53. In comparison to N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; IC50 = 4.15 nM), 17 beta-(N-alkylformamido)-4-azasteroids were potent inhibitors of human type I 5 alpha-reductase, IC50 values of compounds 29, 30, 36, and 37 being measured as 3.05, 0.91, 2.19, and 2.35 nM, respectively. The structure-activity relationships suggest that the type I enzyme has preference for N-substituted straight alkyl side chains of four to five carbon atoms. On the other hand, formamides 32 (N-heptyl) and 33 (N-octyl), in addition to inhibiting the type I enzyme (IC50s = 9.57 and 16.9 nM, respectively), showed also strong inhibitory activity (IC50s = 14.0 and 18.4 nM, respectively) for human type II 5 alpha-reductase, in comparison to N-(1',1'-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (MK-906; IC50 = 4.53 nM). Other compounds in this series showed moderate activities (IC50 > 100 nM) on the type II enzyme. 17 beta-[(N-Alkyl/aryl)alkyl/arylamides] 45, 46, 48, and 51 exhibited highly potent inhibitory activity for human type I 5 alpha-reductase with IC50s of 1.77, 2.42, 2.93, and 5.44 nM, respectively, while moderate to no effect was observed on the type II enzyme (100 < IC50s < 1000 nM), except for compound 48 (IC50 = 3.75 nM). In another substitution pattern, N-aryl/alkylamides were studied; an electron-donating group increased the potency of compound 51, whereas an electron-withdrawing group decreased the potency of compounds 52 and 53 compared to parent compound 50. In addition to their 5 alpha-reductase activities, 17 beta-(N-alkylformamides) were also studied for their inhibitory activities on dihydrotestosterone (DHT)-stimulated proliferation of androgen-sensitive Shionogi mouse mammary carcinoma cells (clone SEM-107).(ABSTRACT TRUNCATED AT 400 WORDS)
|
In vitro inhibition of human Steroid 5-alpha-reductase type 2 in transfected SW-13 cells using [3H]- delta4-Androstenedione as substrate
|
None
|
8.47
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro evaluation of 4-substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-17 beta-carboxamides as 5 alpha-reductase inhibitors and antiandrogens.
Year : 1995
Volume : 38
Issue : 9
First Page : 1456
Last Page : 1461
Authors : Li X, Singh SM, Côté J, Laplante S, Veilleux R, Labrie F.
Abstract : 4-Substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-17 beta-carboxamides with the hydroxy (OH) 3d, mercapto (SH) 3e, chloro (Cl) 3f, and bromo (Br) 3g substituents at the 4-position were prepared in a two-step sequence with overall yields of 21%, 27%, 41%, and 37%, respectively. Compounds 3d-g showed weak inhibitory activity on human type I 5 alpha-reductase (IC50 > or = 700 nM) while they had intermediate inhibitory activity on human type II 5 alpha-reductase at IC50S of 172, 437, 192, and 387 nM, respectively. In androgen-sensitive Shionogi cells, the inhibition of dihydrotestosterone (DHT) stimulatory action on the proliferation of the androgen-sensitive cancer cells by all four compounds was high at IC50S of 170-279 nM compared with 117 nM for hydroxyflutamide. The present data show compounds having both moderate inhibition of human type II 5 alpha-reductase activity and relatively potent antiandrogenic action, two beneficial characteristics in the therapy of androgenic-sensitive diseases.
|
Inhibition of recombinant human Steroid 5-alpha-reductase type 2
|
None
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : 4-Aza-3-oxo-5 alpha-androst-1-ene-17 beta-N-aryl-carboxamides 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.
Year : 1995
Volume : 38
Issue : 17
First Page : 3189
Last Page : 3192
Authors : Bakshi RK, Rasmusson GH, Patel GF, Mosley RT, Chang B, Ellsworth K, Harris GS, Tolman RL.
|
Inhibitory activity measured on human steroid 5-alpha-reductase type 2
|
None
|
0.18
nM
|
|
Journal : J. Med. Chem.
Title : 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 by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent.
Year : 1995
Volume : 38
Issue : 14
First Page : 2621
Last Page : 2627
Authors : Frye SV, Haffner CD, Maloney PR, Hiner RN, Dorsey GF, Noe RA, Unwalla RJ, Batchelor KW, Bramson HN, Stuart JD.
Abstract : A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.
|
Inhibitory activity was measured on rat Steroid 5-alpha-reductase type 2
|
None
|
0.28
nM
|
|
Journal : J. Med. Chem.
Title : 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 by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent.
Year : 1995
Volume : 38
Issue : 14
First Page : 2621
Last Page : 2627
Authors : Frye SV, Haffner CD, Maloney PR, Hiner RN, Dorsey GF, Noe RA, Unwalla RJ, Batchelor KW, Bramson HN, Stuart JD.
Abstract : A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.
|
Binding affinity to recombinant human Steroid 5-alpha-reductase type I was evaluated
|
None
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : 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 by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent.
Year : 1995
Volume : 38
Issue : 14
First Page : 2621
Last Page : 2627
Authors : Frye SV, Haffner CD, Maloney PR, Hiner RN, Dorsey GF, Noe RA, Unwalla RJ, Batchelor KW, Bramson HN, Stuart JD.
Abstract : A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.
|
In vitro inhibition of human Steroid 5-alpha-reductase type I in transfected 293 cells using [3H]- delta4-Androstenedione as substrate
|
None
|
218.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro evaluation of 4-substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-17 beta-carboxamides as 5 alpha-reductase inhibitors and antiandrogens.
Year : 1995
Volume : 38
Issue : 9
First Page : 1456
Last Page : 1461
Authors : Li X, Singh SM, Côté J, Laplante S, Veilleux R, Labrie F.
Abstract : 4-Substituted N-(1,1-dimethylethyl)-3-oxo-4-androstene-17 beta-carboxamides with the hydroxy (OH) 3d, mercapto (SH) 3e, chloro (Cl) 3f, and bromo (Br) 3g substituents at the 4-position were prepared in a two-step sequence with overall yields of 21%, 27%, 41%, and 37%, respectively. Compounds 3d-g showed weak inhibitory activity on human type I 5 alpha-reductase (IC50 > or = 700 nM) while they had intermediate inhibitory activity on human type II 5 alpha-reductase at IC50S of 172, 437, 192, and 387 nM, respectively. In androgen-sensitive Shionogi cells, the inhibition of dihydrotestosterone (DHT) stimulatory action on the proliferation of the androgen-sensitive cancer cells by all four compounds was high at IC50S of 170-279 nM compared with 117 nM for hydroxyflutamide. The present data show compounds having both moderate inhibition of human type II 5 alpha-reductase activity and relatively potent antiandrogenic action, two beneficial characteristics in the therapy of androgenic-sensitive diseases.
|
In vitro inhibition of human steroid 5-alpha-reductase type I in Du-145 cells
|
None
|
26.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro activity of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/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.
Year : 1995
Volume : 38
Issue : 7
First Page : 1158
Last Page : 1173
Authors : Li X, Singh SM, Labrie F.
Abstract : A number of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-3-oxo-4-aza-5 alpha-steroids were prepared from 17 beta-hydroxy-4-azasteroids and evaluated as inhibitors of human 5 alpha-reductase and antagonists of the androgen receptor. Jones' oxidation of 17 beta-hydroxy compounds gave the 17-keto-4-azasteroids, which were treated with amines and NaBH(OAc)3/NaBH3CN to give 17 beta-(N-alkyl/arylamino)-4-azasteroids 10-27. Alternatively, the above-indicated compounds were prepared from amines and 17-keto-4-azasteroids to form imines, which were then reduced with NaBH4. Formylation of amines 10-27 gave 17 beta-(N-alkylformamides) 28-41; however, acylation afforded 17 beta-[(N-alkyl/aryl)alkyl/arylamides] 42-53. In comparison to N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; IC50 = 4.15 nM), 17 beta-(N-alkylformamido)-4-azasteroids were potent inhibitors of human type I 5 alpha-reductase, IC50 values of compounds 29, 30, 36, and 37 being measured as 3.05, 0.91, 2.19, and 2.35 nM, respectively. The structure-activity relationships suggest that the type I enzyme has preference for N-substituted straight alkyl side chains of four to five carbon atoms. On the other hand, formamides 32 (N-heptyl) and 33 (N-octyl), in addition to inhibiting the type I enzyme (IC50s = 9.57 and 16.9 nM, respectively), showed also strong inhibitory activity (IC50s = 14.0 and 18.4 nM, respectively) for human type II 5 alpha-reductase, in comparison to N-(1',1'-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (MK-906; IC50 = 4.53 nM). Other compounds in this series showed moderate activities (IC50 > 100 nM) on the type II enzyme. 17 beta-[(N-Alkyl/aryl)alkyl/arylamides] 45, 46, 48, and 51 exhibited highly potent inhibitory activity for human type I 5 alpha-reductase with IC50s of 1.77, 2.42, 2.93, and 5.44 nM, respectively, while moderate to no effect was observed on the type II enzyme (100 < IC50s < 1000 nM), except for compound 48 (IC50 = 3.75 nM). In another substitution pattern, N-aryl/alkylamides were studied; an electron-donating group increased the potency of compound 51, whereas an electron-withdrawing group decreased the potency of compounds 52 and 53 compared to parent compound 50. In addition to their 5 alpha-reductase activities, 17 beta-(N-alkylformamides) were also studied for their inhibitory activities on dihydrotestosterone (DHT)-stimulated proliferation of androgen-sensitive Shionogi mouse mammary carcinoma cells (clone SEM-107).(ABSTRACT TRUNCATED AT 400 WORDS)
|
Inhibition of recombinant human Steroid 5-alpha-reductase type I
|
None
|
52.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Aza-3-oxo-5 alpha-androst-1-ene-17 beta-N-aryl-carboxamides 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.
Year : 1995
Volume : 38
Issue : 17
First Page : 3189
Last Page : 3192
Authors : Bakshi RK, Rasmusson GH, Patel GF, Mosley RT, Chang B, Ellsworth K, Harris GS, Tolman RL.
|
Apparent inhibition constant towards human Steroid 5-alpha-reductase type I
|
None
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A non-steroidal diene acid inhibitor of human type 2 stereoid 5-reductase
Year : 1994
Volume : 4
Issue : 19
First Page : 2327
Last Page : 2330
Authors : Abell AD, Brandt M, Levy MA, Holt DA
|
Inhibition of recombinant Steroid 5-alpha-reductase type I was evaluated as binding affinity (in vitro)
|
None
|
6.8
nM
|
|
Journal : J. Med. Chem.
Title : 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 by 6-azaandrost-4-en-3-ones: optimization of the C17 substituent.
Year : 1995
Volume : 38
Issue : 14
First Page : 2621
Last Page : 2627
Authors : Frye SV, Haffner CD, Maloney PR, Hiner RN, Dorsey GF, Noe RA, Unwalla RJ, Batchelor KW, Bramson HN, Stuart JD.
Abstract : A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.
|
Compound was evaluated for the inhibition of human Steroid 5-alpha-reductase type 1 from recombinant CHO cells
|
None
|
911.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of benzo[c]quinolizin-3-ones: selective non-steroidal inhibitors of steroid 5 alpha-reductase 1.
Year : 1998
Volume : 8
Issue : 20
First Page : 2871
Last Page : 2876
Authors : Guarna A, Occhiato EG, Scarpi D, Tsai R, Danza G, Comerci A, Mancina R, Serio M.
Abstract : A short and efficient synthesis of novel benzo[c]quinolizin-3-one derivatives is described. The synthesis is based on the tandem Mannich-Michael cyclization between 2-silyloxy-1,3-butadienes and a N-t-Boc iminium ion. The prepared derivatives are selective inhibitors of human steroid 5 alpha-reductase isoenzyme 1, thus having potential application as drugs for treatment of male pattern baldness and other DHT-dependent skin disorders.
|
Compound was tested for the inhibitory activity against Steroid 5-alpha-reductase type 1 in rat
|
None
|
4.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure activity relationship study of known inhibitors of the enzyme 5 alpha-reductase (5AR).
Year : 1998
Volume : 8
Issue : 5
First Page : 409
Last Page : 414
Authors : Ahmed S, Denison S.
Abstract : Preliminary results of a modelling study of both steroidal and non-steroidal inhibitors of 5 alpha-reductase (5AR) are described in order to elucidate the essential structural requirements needed for the design of novel non-steroidal inhibitors. The study suggests that: (i) there is a requirement for groups to mimic the C(3) = O of the steroid substrate A-ring; (ii) the area of the active site about the C(17)-OH position of the substrate does not appear to possess hydrogen bonding groups and is unrestricted.
|
Compound was evaluated for the inhibition of human Steroid 5-alpha-reductase type 2 receptor from human prostate homogenates
|
None
|
1.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of benzo[c]quinolizin-3-ones: selective non-steroidal inhibitors of steroid 5 alpha-reductase 1.
Year : 1998
Volume : 8
Issue : 20
First Page : 2871
Last Page : 2876
Authors : Guarna A, Occhiato EG, Scarpi D, Tsai R, Danza G, Comerci A, Mancina R, Serio M.
Abstract : A short and efficient synthesis of novel benzo[c]quinolizin-3-one derivatives is described. The synthesis is based on the tandem Mannich-Michael cyclization between 2-silyloxy-1,3-butadienes and a N-t-Boc iminium ion. The prepared derivatives are selective inhibitors of human steroid 5 alpha-reductase isoenzyme 1, thus having potential application as drugs for treatment of male pattern baldness and other DHT-dependent skin disorders.
|
Evaluated for the inhibitory activity against human steroid 5-alpha-reductase type 2 from human BPH tissue at 210 nM of testosterone
|
None
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of novel steroidal oxime inhibitors of P450 17 (17 alpha-hydroxylase/C17-20-lyase) and 5 alpha-reductase types 1 and 2.
Year : 2000
Volume : 43
Issue : 22
First Page : 4266
Last Page : 4277
Authors : Hartmann RW, Hector M, Haidar S, Ehmer PB, Reichert W, Jose J.
Abstract : 17 alpha-Hydroxylase/C17-20-lyase (P450 17, CYP 17) and 5 alpha-reductase are the key enzymes in androgen biosynthesis and targets for the treatment of prostate cancer and benign prostatic hyperplasia. In the search of inhibitors for both enzymes, 23 pregnenolone- or progesterone-based steroids were synthesized bearing an oxime group connected directly or via a spacer to the steroidal D-ring. Tested for inhibition of human and rat P450 17, some pregnenolone (9, 11, 14) and a series of progesterone compounds (17-20) turned out to be highly active inhibitors of the human enzyme. The most active compound was Z-21-hydroxyiminopregna-5, 17(20)-dien-3 beta-ol (9) showing K(i) values of 44 and 3.4 nM for the human and rat enzymes, respectively, and a type II UV-difference spectrum indicating a coordinate bond between the oxime group and the heme iron. In contrast to the pregnenolones which showed no inhibition of 5 alpha-reductase isozymes 1 and 2, the progesterones 16, 17, 20, 21, and 23 showed marked inhibition, especially toward the type 2 enzyme. Compounds 17 and 20 were identified as potent dual inhibitors of both P450 17 and 5 alpha-reductase. Tested for selectivity, the most potent P450 17 inhibitors 9, 10, and 14 showed no or only marginal inhibition of P450 arom, P450 scc, and P450 TxA(2). Selected compounds were tested for inhibition of the target enzymes using whole-cell assays. Compounds 9-11 strongly inhibited P450 17 being coexpressed with NADPH-P450 reductase in E. coli cells, and 16, 20, and 23 markedly inhibited 5 alpha-reductase expressed in HEK 293 cells. Tested for in vivo activity, 9 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats after 2 and 6 h by 57% and 44%.
|
Inhibition of Human steroid 5-alpha-reductase type II expressed in HEK293 cells
|
Homo sapiens
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of novel steroidal oxime inhibitors of P450 17 (17 alpha-hydroxylase/C17-20-lyase) and 5 alpha-reductase types 1 and 2.
Year : 2000
Volume : 43
Issue : 22
First Page : 4266
Last Page : 4277
Authors : Hartmann RW, Hector M, Haidar S, Ehmer PB, Reichert W, Jose J.
Abstract : 17 alpha-Hydroxylase/C17-20-lyase (P450 17, CYP 17) and 5 alpha-reductase are the key enzymes in androgen biosynthesis and targets for the treatment of prostate cancer and benign prostatic hyperplasia. In the search of inhibitors for both enzymes, 23 pregnenolone- or progesterone-based steroids were synthesized bearing an oxime group connected directly or via a spacer to the steroidal D-ring. Tested for inhibition of human and rat P450 17, some pregnenolone (9, 11, 14) and a series of progesterone compounds (17-20) turned out to be highly active inhibitors of the human enzyme. The most active compound was Z-21-hydroxyiminopregna-5, 17(20)-dien-3 beta-ol (9) showing K(i) values of 44 and 3.4 nM for the human and rat enzymes, respectively, and a type II UV-difference spectrum indicating a coordinate bond between the oxime group and the heme iron. In contrast to the pregnenolones which showed no inhibition of 5 alpha-reductase isozymes 1 and 2, the progesterones 16, 17, 20, 21, and 23 showed marked inhibition, especially toward the type 2 enzyme. Compounds 17 and 20 were identified as potent dual inhibitors of both P450 17 and 5 alpha-reductase. Tested for selectivity, the most potent P450 17 inhibitors 9, 10, and 14 showed no or only marginal inhibition of P450 arom, P450 scc, and P450 TxA(2). Selected compounds were tested for inhibition of the target enzymes using whole-cell assays. Compounds 9-11 strongly inhibited P450 17 being coexpressed with NADPH-P450 reductase in E. coli cells, and 16, 20, and 23 markedly inhibited 5 alpha-reductase expressed in HEK 293 cells. Tested for in vivo activity, 9 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats after 2 and 6 h by 57% and 44%.
|
Inhibition of Steroid 5-alpha-reductase type 2 from human benign prostatic hyperplasia (BPH) tissue
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 2'-substituted 4-(4'-carboxy- or 4'-carboxymethylbenzylidene)-N-acylpiperidines: highly potent and in vivo active steroid 5alpha-reductase type 2 inhibitors.
Year : 2002
Volume : 45
Issue : 16
First Page : 3406
Last Page : 3417
Authors : Picard F, Barassin S, Mokhtarian A, Hartmann RW.
Abstract : Sixteen compounds derived from N-acyl-4-benzylidenepiperidine-4'-carboxylic acids were synthesized and evaluated for inhibition of rat and human steroid 5alpha-reductase isozymes types 1 and 2. In the dicyclohexylacetyl series, fluorination in the 2-position of the benzene nucleus (15), exchange of the carboxy group by a carboxymethyl moiety (20), and combination of both structural modifications (25) led to highly active inhibitors of the human type 2 isozyme (IC(50) values: 15, 11 nM; 20, 6 nM; 25, 7 nM; finasteride, 5 nM). In vivo all compounds tested markedly reduced the prostate weights in castrated testosterone-treated rats. Oral activity was shown for compound 7. From the finding that compound 15 is active in the rat, although it is a rather poor inhibitor of the rat enzyme and is a strong inhibitor of the human enzyme, it is concluded that it should be highly potent in men.
|
Inhibitory activity against steroid 5-alpha-reductase type 2 in human prostate homogenates
|
None
|
2.2
nM
|
|
Journal : J. Med. Chem.
Title : Benzo[c]quinolizin-3-ones: a novel class of potent and selective nonsteroidal inhibitors of human steroid 5alpha-reductase 1.
Year : 2000
Volume : 43
Issue : 20
First Page : 3718
Last Page : 3735
Authors : Guarna A, Machetti F, Occhiato EG, Scarpi D, Comerci A, Danza G, Mancina R, Serio M, Hardy K.
Abstract : The synthesis and biological evaluation of a series of novel, selective inhibitors of isoenzyme 1 of human 5alpha-reductase (5alphaR) (EC 1.3.99.5) are reported. The inhibitors are 4aH- (19-29) or 1H-tetrahydrobenzo[c]quinolizin-3-ones (35-47) bearing at positions 1, 4, 5, and 6 a methyl group and at position 8 a hydrogen, methyl group, or chlorine atom. All these compounds were tested toward 5alphaR-1 and 5alphaR-2 expressed in CHO cells (CHO 1827 and CHO 1829, respectively) resulting in selective inhibitors of the type 1 isoenzyme, with inhibitory potencies (IC(50)) ranging from 7.6 to 9100 nM. The inhibitors of the 4aH-series, having a double bond at position 1,2, were generally less active than the corresponding inhibitors of the 1H-series having the double bond at position 4,4a on the A ring. The presence of a methyl group at position 4 (as in compounds 39-40 and 45-47), associated with a substituent at position 8, determined the highest inhibition potency (IC(50) from 7.6 to 20 nM). Compounds 39 and 40, having K(i) values of 5.8+/-1.8 and 2.7+/-0.6 nM, respectively, toward 5alphaR-1 expressed in CHO cells, were also tested toward native 5alphaR-1 in human scalp and 5alphaR-2 in human prostate homogenates, in comparison with finasteride and the known 5alphaR-1-selective inhibitor LY191704, and their mechanism of inhibition was determined. They both inhibited the enzyme through a reversible competitive mechanism and again were selective inhibitors of 5alphaR-1 with IC(50) values of 41 nM. These specific features make these inhibitors suitable candidates for further development as drugs in the treatment of DHT-dependent disorders such as acne and androgenic alopecia in men and hirsutism in women.
|
Apparent inhibition constant towards human Steroid 5-alpha-reductase type 2
|
None
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A non-steroidal diene acid inhibitor of human type 2 stereoid 5-reductase
Year : 1994
Volume : 4
Issue : 19
First Page : 2327
Last Page : 2330
Authors : Abell AD, Brandt M, Levy MA, Holt DA
|
Inhibition of Steroid 5-alpha-reductase type 2 of rat ventral prostate (RVP)
|
Rattus norvegicus
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 2'-substituted 4-(4'-carboxy- or 4'-carboxymethylbenzylidene)-N-acylpiperidines: highly potent and in vivo active steroid 5alpha-reductase type 2 inhibitors.
Year : 2002
Volume : 45
Issue : 16
First Page : 3406
Last Page : 3417
Authors : Picard F, Barassin S, Mokhtarian A, Hartmann RW.
Abstract : Sixteen compounds derived from N-acyl-4-benzylidenepiperidine-4'-carboxylic acids were synthesized and evaluated for inhibition of rat and human steroid 5alpha-reductase isozymes types 1 and 2. In the dicyclohexylacetyl series, fluorination in the 2-position of the benzene nucleus (15), exchange of the carboxy group by a carboxymethyl moiety (20), and combination of both structural modifications (25) led to highly active inhibitors of the human type 2 isozyme (IC(50) values: 15, 11 nM; 20, 6 nM; 25, 7 nM; finasteride, 5 nM). In vivo all compounds tested markedly reduced the prostate weights in castrated testosterone-treated rats. Oral activity was shown for compound 7. From the finding that compound 15 is active in the rat, although it is a rather poor inhibitor of the rat enzyme and is a strong inhibitor of the human enzyme, it is concluded that it should be highly potent in men.
|
Evaluated for the inhibitory activity against human steroid 5-alpha-reductase type I in human DU-145 cell assay at 5 nM of androstenedione
|
None
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of novel steroidal oxime inhibitors of P450 17 (17 alpha-hydroxylase/C17-20-lyase) and 5 alpha-reductase types 1 and 2.
Year : 2000
Volume : 43
Issue : 22
First Page : 4266
Last Page : 4277
Authors : Hartmann RW, Hector M, Haidar S, Ehmer PB, Reichert W, Jose J.
Abstract : 17 alpha-Hydroxylase/C17-20-lyase (P450 17, CYP 17) and 5 alpha-reductase are the key enzymes in androgen biosynthesis and targets for the treatment of prostate cancer and benign prostatic hyperplasia. In the search of inhibitors for both enzymes, 23 pregnenolone- or progesterone-based steroids were synthesized bearing an oxime group connected directly or via a spacer to the steroidal D-ring. Tested for inhibition of human and rat P450 17, some pregnenolone (9, 11, 14) and a series of progesterone compounds (17-20) turned out to be highly active inhibitors of the human enzyme. The most active compound was Z-21-hydroxyiminopregna-5, 17(20)-dien-3 beta-ol (9) showing K(i) values of 44 and 3.4 nM for the human and rat enzymes, respectively, and a type II UV-difference spectrum indicating a coordinate bond between the oxime group and the heme iron. In contrast to the pregnenolones which showed no inhibition of 5 alpha-reductase isozymes 1 and 2, the progesterones 16, 17, 20, 21, and 23 showed marked inhibition, especially toward the type 2 enzyme. Compounds 17 and 20 were identified as potent dual inhibitors of both P450 17 and 5 alpha-reductase. Tested for selectivity, the most potent P450 17 inhibitors 9, 10, and 14 showed no or only marginal inhibition of P450 arom, P450 scc, and P450 TxA(2). Selected compounds were tested for inhibition of the target enzymes using whole-cell assays. Compounds 9-11 strongly inhibited P450 17 being coexpressed with NADPH-P450 reductase in E. coli cells, and 16, 20, and 23 markedly inhibited 5 alpha-reductase expressed in HEK 293 cells. Tested for in vivo activity, 9 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats after 2 and 6 h by 57% and 44%.
|
Inhibition of Human steroid 5-alpha-reductase type I expressed in HEK293 cells
|
Homo sapiens
|
540.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of novel steroidal oxime inhibitors of P450 17 (17 alpha-hydroxylase/C17-20-lyase) and 5 alpha-reductase types 1 and 2.
Year : 2000
Volume : 43
Issue : 22
First Page : 4266
Last Page : 4277
Authors : Hartmann RW, Hector M, Haidar S, Ehmer PB, Reichert W, Jose J.
Abstract : 17 alpha-Hydroxylase/C17-20-lyase (P450 17, CYP 17) and 5 alpha-reductase are the key enzymes in androgen biosynthesis and targets for the treatment of prostate cancer and benign prostatic hyperplasia. In the search of inhibitors for both enzymes, 23 pregnenolone- or progesterone-based steroids were synthesized bearing an oxime group connected directly or via a spacer to the steroidal D-ring. Tested for inhibition of human and rat P450 17, some pregnenolone (9, 11, 14) and a series of progesterone compounds (17-20) turned out to be highly active inhibitors of the human enzyme. The most active compound was Z-21-hydroxyiminopregna-5, 17(20)-dien-3 beta-ol (9) showing K(i) values of 44 and 3.4 nM for the human and rat enzymes, respectively, and a type II UV-difference spectrum indicating a coordinate bond between the oxime group and the heme iron. In contrast to the pregnenolones which showed no inhibition of 5 alpha-reductase isozymes 1 and 2, the progesterones 16, 17, 20, 21, and 23 showed marked inhibition, especially toward the type 2 enzyme. Compounds 17 and 20 were identified as potent dual inhibitors of both P450 17 and 5 alpha-reductase. Tested for selectivity, the most potent P450 17 inhibitors 9, 10, and 14 showed no or only marginal inhibition of P450 arom, P450 scc, and P450 TxA(2). Selected compounds were tested for inhibition of the target enzymes using whole-cell assays. Compounds 9-11 strongly inhibited P450 17 being coexpressed with NADPH-P450 reductase in E. coli cells, and 16, 20, and 23 markedly inhibited 5 alpha-reductase expressed in HEK 293 cells. Tested for in vivo activity, 9 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats after 2 and 6 h by 57% and 44%.
|
In vitro inhibitory activity against Steroid 5-alpha-reductase type I of human DU 145 prostatic tumor cell line
|
None
|
41.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 2'-substituted 4-(4'-carboxy- or 4'-carboxymethylbenzylidene)-N-acylpiperidines: highly potent and in vivo active steroid 5alpha-reductase type 2 inhibitors.
Year : 2002
Volume : 45
Issue : 16
First Page : 3406
Last Page : 3417
Authors : Picard F, Barassin S, Mokhtarian A, Hartmann RW.
Abstract : Sixteen compounds derived from N-acyl-4-benzylidenepiperidine-4'-carboxylic acids were synthesized and evaluated for inhibition of rat and human steroid 5alpha-reductase isozymes types 1 and 2. In the dicyclohexylacetyl series, fluorination in the 2-position of the benzene nucleus (15), exchange of the carboxy group by a carboxymethyl moiety (20), and combination of both structural modifications (25) led to highly active inhibitors of the human type 2 isozyme (IC(50) values: 15, 11 nM; 20, 6 nM; 25, 7 nM; finasteride, 5 nM). In vivo all compounds tested markedly reduced the prostate weights in castrated testosterone-treated rats. Oral activity was shown for compound 7. From the finding that compound 15 is active in the rat, although it is a rather poor inhibitor of the rat enzyme and is a strong inhibitor of the human enzyme, it is concluded that it should be highly potent in men.
|
Inhibitory concentration against human recombinant steroid 5-alpha-reductase type I in stably transfected chinese hamster ovary (CHO) 1827 cells using [3H]testosterone.
|
None
|
911.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological activity, and three-dimensional quantitative structure-activity relationship model for a series of benzo[c]quinolizin-3-ones, nonsteroidal inhibitors of human steroid 5alpha-reductase 1.
Year : 2004
Volume : 47
Issue : 14
First Page : 3546
Last Page : 3560
Authors : Occhiato EG, Ferrali A, Menchi G, Guarna A, Danza G, Comerci A, Mancina R, Serio M, Garotta G, Cavalli A, De Vivo M, Recanatini M.
Abstract : New 5alpha-reductase 1 (5alphaR-1) inhibitors were designed to complete a consistent set of analogues suitable for a 3D QSAR study. These compounds were synthesized by a modification of the aza-Robinson annulation, further functionalized by Pd-catalyzed cross-coupling processes, and were tested with human 5alphaR-1 expressed in Chinese hamster ovary 1827 cells. It turned out that the potency of the resulting inhibitors was strongly dependent on the type of substitution at the 8 position, with the IC(50) values ranging from 8.1 to 1050 nM. The construction of this homogeneous set of molecules allowed a 3D QSAR study. In particular, comparative molecular field analysis (CoMFA) was used to correlate the potency of the inhibitors with their physicochemical features. Highly accurate evaluations of the atomic point charges were carried out by means of quantum chemical calculations at the DFT/B3LYP level of theory followed by the RESP fitting procedure. It turned out that increasing the reliability of electrostatic parameters greatly affected the statistical results of the QSAR analysis. The 3D QSAR model proposed could be very useful in the further development of 5alphaR-1 inhibitors, which are suitable candidates to be evaluated as drugs in the treatment of 5alphaR-1 related diseases such as acne and alopecia in men and hirsutism in women.
|
Inhibitory activity against recombinant Steroid 5-alpha-reductase type I expressed in CHO cells
|
None
|
366.0
nM
|
|
Journal : J. Med. Chem.
Title : Benzo[c]quinolizin-3-ones: a novel class of potent and selective nonsteroidal inhibitors of human steroid 5alpha-reductase 1.
Year : 2000
Volume : 43
Issue : 20
First Page : 3718
Last Page : 3735
Authors : Guarna A, Machetti F, Occhiato EG, Scarpi D, Comerci A, Danza G, Mancina R, Serio M, Hardy K.
Abstract : The synthesis and biological evaluation of a series of novel, selective inhibitors of isoenzyme 1 of human 5alpha-reductase (5alphaR) (EC 1.3.99.5) are reported. The inhibitors are 4aH- (19-29) or 1H-tetrahydrobenzo[c]quinolizin-3-ones (35-47) bearing at positions 1, 4, 5, and 6 a methyl group and at position 8 a hydrogen, methyl group, or chlorine atom. All these compounds were tested toward 5alphaR-1 and 5alphaR-2 expressed in CHO cells (CHO 1827 and CHO 1829, respectively) resulting in selective inhibitors of the type 1 isoenzyme, with inhibitory potencies (IC(50)) ranging from 7.6 to 9100 nM. The inhibitors of the 4aH-series, having a double bond at position 1,2, were generally less active than the corresponding inhibitors of the 1H-series having the double bond at position 4,4a on the A ring. The presence of a methyl group at position 4 (as in compounds 39-40 and 45-47), associated with a substituent at position 8, determined the highest inhibition potency (IC(50) from 7.6 to 20 nM). Compounds 39 and 40, having K(i) values of 5.8+/-1.8 and 2.7+/-0.6 nM, respectively, toward 5alphaR-1 expressed in CHO cells, were also tested toward native 5alphaR-1 in human scalp and 5alphaR-2 in human prostate homogenates, in comparison with finasteride and the known 5alphaR-1-selective inhibitor LY191704, and their mechanism of inhibition was determined. They both inhibited the enzyme through a reversible competitive mechanism and again were selective inhibitors of 5alphaR-1 with IC(50) values of 41 nM. These specific features make these inhibitors suitable candidates for further development as drugs in the treatment of DHT-dependent disorders such as acne and androgenic alopecia in men and hirsutism in women.
|
Inhibition of Steroid 5-alpha-reductase type I from rat ventral prostate (RVP)
|
Rattus norvegicus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of 2'-substituted 4-(4'-carboxy- or 4'-carboxymethylbenzylidene)-N-acylpiperidines: highly potent and in vivo active steroid 5alpha-reductase type 2 inhibitors.
Year : 2002
Volume : 45
Issue : 16
First Page : 3406
Last Page : 3417
Authors : Picard F, Barassin S, Mokhtarian A, Hartmann RW.
Abstract : Sixteen compounds derived from N-acyl-4-benzylidenepiperidine-4'-carboxylic acids were synthesized and evaluated for inhibition of rat and human steroid 5alpha-reductase isozymes types 1 and 2. In the dicyclohexylacetyl series, fluorination in the 2-position of the benzene nucleus (15), exchange of the carboxy group by a carboxymethyl moiety (20), and combination of both structural modifications (25) led to highly active inhibitors of the human type 2 isozyme (IC(50) values: 15, 11 nM; 20, 6 nM; 25, 7 nM; finasteride, 5 nM). In vivo all compounds tested markedly reduced the prostate weights in castrated testosterone-treated rats. Oral activity was shown for compound 7. From the finding that compound 15 is active in the rat, although it is a rather poor inhibitor of the rat enzyme and is a strong inhibitor of the human enzyme, it is concluded that it should be highly potent in men.
|
Compound was tested in vitro for inhibitory activity against 5-alpha reductase isozyme homogenated from transfected Namalwa
|
None
|
580.0
nM
|
|
Journal : J. Med. Chem.
Title : Indole derivatives as a new class of steroid 5 alpha-reductase inhibitors.
Year : 1996
Volume : 39
Issue : 26
First Page : 5047
Last Page : 5052
Authors : Takami H, Koshimura H, Kishibayashi N, Ishii A, Nonaka H, Aoyama S, Kase H, Kumazawa T.
Abstract : A series of indole derivatives with varied substituents on the alpha, beta-unsaturated double bond were synthesized and evaluated for their ability to inhibit rat prostatic 5 alpha-reductase. Compounds possessing an ethyl substituent at the beta-position of the double bond showed potent inhibitory activity. Among them, (Z)-4-{2-[[3-[1-(4,4'-difluorobenzhydryl)indol-5-yl]-2-pentenoy l]- amino]phenoxy}butyric acid (16, KF20405) showed the maximum potency with an IC50 value of 0.48 +/- 0.086 nM, which was 20-fold higher potency than 1 (MK-906). Compound 16 effectively inhibited DHT production 4 h after a 3 mg/kg oral administration. Several potent indole derivatives, 1 and 2 ((+/-)-ONO-3805), were tested versus rat and human isozymes. Nonsteroidal inhibitors such as indole derivatives and 2 were 2-3 orders of magnitude less potent for human type 2 isozyme than steroidal inhibitor 1 and expressed a significant species deference for these isozymes.
|
Inhibitory activity of compound towards 5-alpha reductase from rat at 100 nM concentration
|
None
|
10.0
%
|
|
Journal : J. Med. Chem.
Title : Indole derivatives as a new class of steroid 5 alpha-reductase inhibitors.
Year : 1996
Volume : 39
Issue : 26
First Page : 5047
Last Page : 5052
Authors : Takami H, Koshimura H, Kishibayashi N, Ishii A, Nonaka H, Aoyama S, Kase H, Kumazawa T.
Abstract : A series of indole derivatives with varied substituents on the alpha, beta-unsaturated double bond were synthesized and evaluated for their ability to inhibit rat prostatic 5 alpha-reductase. Compounds possessing an ethyl substituent at the beta-position of the double bond showed potent inhibitory activity. Among them, (Z)-4-{2-[[3-[1-(4,4'-difluorobenzhydryl)indol-5-yl]-2-pentenoy l]- amino]phenoxy}butyric acid (16, KF20405) showed the maximum potency with an IC50 value of 0.48 +/- 0.086 nM, which was 20-fold higher potency than 1 (MK-906). Compound 16 effectively inhibited DHT production 4 h after a 3 mg/kg oral administration. Several potent indole derivatives, 1 and 2 ((+/-)-ONO-3805), were tested versus rat and human isozymes. Nonsteroidal inhibitors such as indole derivatives and 2 were 2-3 orders of magnitude less potent for human type 2 isozyme than steroidal inhibitor 1 and expressed a significant species deference for these isozymes.
|
Inhibition of type 1 steroid-5-alpha-reductase
|
None
|
52.0
nM
|
|
Journal : J. Med. Chem.
Title : 4,7 beta-Dimethyl-4-azacholestan-3-one (MK-386) and related 4-azasteroids as selective inhibitors of human type 1 5 alpha-reductase.
Year : 1994
Volume : 37
Issue : 23
First Page : 3871
Last Page : 3874
Authors : Bakshi RK, Patel GF, Rasmusson GH, Baginsky WF, Cimis G, Ellsworth K, Chang B, Bull H, Tolman RL, Harris GS.
|
In vitro inhibitory activity against human type 1 5-alpha reductase
|
None
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : 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.
Year : 1994
Volume : 37
Issue : 15
First Page : 2352
Last Page : 2360
Authors : Frye SV, Haffner CD, Maloney PR, Mook RA, Dorsey GF, Hiner RN, Cribbs CM, Wheeler TN, Ray JA, Andrews RC.
Abstract : 6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.
|
Inhibitory activity against 5-alpha-reductase type 1 in cell culture system using LNCaP cells (androgen-sensitive human prostatic cancer cell line)
|
None
|
19.8
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel class of inhibitors for steroid 5alpha-reductase: synthesis and evaluation of umbelliferone derivatives.
Year : 2001
Volume : 11
Issue : 17
First Page : 2361
Last Page : 2364
Authors : Fan G, Mar W, Park MK, Choi EW, Kim K, Kim S.
Abstract : A series of umbelliferone derivatives was prepared and their 5alpha-reductase type 1 inhibitory activities were evaluated in cell culture systems. Our studies have identified a new series of potent 5alpha-reductase type 1 inhibitors and provided the basis for further development for the treatment of human endocrine disorders associated with overproduction of DHT by 5alpha-reductase type 1. The preliminary structure-activity relationship was described to elucidate the essential structural requirements.
|
Binding affinity for human 5 alpha reductase 1 isozyme
|
Homo sapiens
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacological options in the treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 9
First Page : 1293
Last Page : 1315
Authors : Kenny B, Ballard S, Blagg J, Fox D.
|
Inhibitory activity against human 5-alpha Reductase-1 expressed in DU-145 cells
|
None
|
42.0
nM
|
|
Journal : J. Med. Chem.
Title : 19-nor-10-azasteroids: a novel class of inhibitors for human steroid 5alpha-reductases 1 and 2.
Year : 1997
Volume : 40
Issue : 7
First Page : 1112
Last Page : 1129
Authors : Guarna A, Belle C, Machetti F, Occhiato EG, Payne AH, Cassiani C, Comerci A, Danza G, De Bellis A, Dini S, Marrucci A, Serio M.
Abstract : Steroid 5alpha-reductase is a system of two isozymes (5alphaR-1 and 5alphaR-2) which catalyzes the NADPH-dependent reduction of testosterone to dihydrotestosterone in many androgen sensitive tissues and which is related to several human endocrine diseases such as benign prostatic hyperplasia (BPH), prostatic cancer, acne, alopecia, pattern baldness in men and hirsutism in women. The discovery of new potent and selective 5alphaR inhibitors is thus of great interest for pharmaceutical treatment of these diseases. The synthesis of a novel class of inhibitors for human 5alphaR-1 and 5alphaR-2, having the 19-nor-10-azasteroid skeleton, is described. The inhibitory potency of the 19-nor-10-azasteroids was determined in homogenates of human hypertrophic prostates toward 5alphaR-2 and in DU-145 human prostatic adenocarcinoma cells toward 5alphaR-1, in comparison with finasteride (IC50 = 3 nM for 5alphaR-2 and approximately 42 nM for 5alphaR-1), a drug which is currently used for BPH treatment. The inhibition potency was dependent on the type of substituent at position 17 and on the presence and position of the unsaturation in the A and C rings. delta9(11)-19-Nor-10-azaandrost-4-ene-3,17-dione (or 10-azaestra-4,9(11)-diene-3,17-dione) (4a) and 19-nor-10-azaandrost-4-ene-3,17-dione (5) were weak inhibitors of 5alphaR-2 (IC50 = 4.6 and 4.4 microM, respectively) but more potent inhibitors of 5alphaR-1 (IC50 = 263 and 299 nM, respectively), whereas 19-nor-10-aza-5alpha-androstane-3,17-dione (7) was inactive for both the isoenzymes. The best result was achieved with the 9:1 mixture of delta9(11)- and delta8(9)-17beta-(N-tert-butylcarbamoyl)-19-nor-10-aza-4- androsten-3-one (10a,b) which was a good inhibitor of 5alphaR-1 and 5alphaR-2 (IC50 = 127 and 122 nM, respectively), with a potency very close to that of finasteride. The results of ab initio calculations suggest that the inhibition potency of 19-nor-10-azasteroids could be directly related to the nucleophilicity of the carbonyl group in the 3-position.
|
Compound was tested for inhibition of Type I 5-alpha-reductase in Human genital skin (Hs68) foreskin fibroblast cells.
|
None
|
62.0
nM
|
|
Journal : J. Med. Chem.
Title : Nonsteroidal inhibitors of human type I steroid 5-alpha-reductase.
Year : 1993
Volume : 36
Issue : 3
First Page : 421
Last Page : 423
Authors : Jones CD, Audia JE, Lawhorn DE, McQuaid LA, Neubauer BL, Pike AJ, Pennington PA, Stamm NB, Toomey RE, Hirsch KS.
|
Compound was tested for inhibition of Type II 5-alpha-reductase in Human Prostate Homogenates (HPH).
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Nonsteroidal inhibitors of human type I steroid 5-alpha-reductase.
Year : 1993
Volume : 36
Issue : 3
First Page : 421
Last Page : 423
Authors : Jones CD, Audia JE, Lawhorn DE, McQuaid LA, Neubauer BL, Pike AJ, Pennington PA, Stamm NB, Toomey RE, Hirsch KS.
|
Inhibitory concentration against human recombinant steroid 5-alpha-reductase type 2 in stably transfected chinese hamster ovary 1827 cells using [3H]testosterone
|
None
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological activity, and three-dimensional quantitative structure-activity relationship model for a series of benzo[c]quinolizin-3-ones, nonsteroidal inhibitors of human steroid 5alpha-reductase 1.
Year : 2004
Volume : 47
Issue : 14
First Page : 3546
Last Page : 3560
Authors : Occhiato EG, Ferrali A, Menchi G, Guarna A, Danza G, Comerci A, Mancina R, Serio M, Garotta G, Cavalli A, De Vivo M, Recanatini M.
Abstract : New 5alpha-reductase 1 (5alphaR-1) inhibitors were designed to complete a consistent set of analogues suitable for a 3D QSAR study. These compounds were synthesized by a modification of the aza-Robinson annulation, further functionalized by Pd-catalyzed cross-coupling processes, and were tested with human 5alphaR-1 expressed in Chinese hamster ovary 1827 cells. It turned out that the potency of the resulting inhibitors was strongly dependent on the type of substitution at the 8 position, with the IC(50) values ranging from 8.1 to 1050 nM. The construction of this homogeneous set of molecules allowed a 3D QSAR study. In particular, comparative molecular field analysis (CoMFA) was used to correlate the potency of the inhibitors with their physicochemical features. Highly accurate evaluations of the atomic point charges were carried out by means of quantum chemical calculations at the DFT/B3LYP level of theory followed by the RESP fitting procedure. It turned out that increasing the reliability of electrostatic parameters greatly affected the statistical results of the QSAR analysis. The 3D QSAR model proposed could be very useful in the further development of 5alphaR-1 inhibitors, which are suitable candidates to be evaluated as drugs in the treatment of 5alphaR-1 related diseases such as acne and alopecia in men and hirsutism in women.
|
Inhibition of [1-beta-2beta-3H]- -testosterone binding to human steroid 5-alpha-reductase type 2 of BPH tissue at 10 uM
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model.
Year : 2005
Volume : 48
Issue : 8
First Page : 2972
Last Page : 2984
Authors : Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman D, Farquhar R, Guo Z, Qiu Y, Brodie AM.
Abstract : New chemical entities, steroidal C-17 benzoazoles (5, 6, 9 and 10) and pyrazines (14 and 15) were rationally designed and synthesized. The key reaction for synthesis of the benzoazoles involved the nucleophilic vinylic "addition-elimination" substitution reaction of 3beta-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and benzoazole nucleophiles, while that for synthesis of pyrazines involved palladium-catalyzed cross-coupling reaction of 17-iodoandrosta-5,16-dien-3beta-ol (13) with tributylstannyl diazines. Some of the compounds were shown to be potent inhibitors of human CYP17 enzyme as well as potent antagonist of both wild type and mutant androgen receptors (AR). The most potent CYP17 inhibitors were 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (5, code named VN/124-1), 3beta-hydroxy-17-(5(1)-pyrimidyl)androsta-5,16-diene (15) and 17-(1H-benzimidazole-1-yl)androsta-4,16-dien-3-one (6), with IC(50) values of 300, 500 and 915 nM, respectively. Compounds 5, 6, 14 and 15 were effective at preventing binding of (3)H-R1881 (methyltrienolone, a stable synthetic androgen) to both the mutant LNCaP AR and the wild-type AR, but with a 2.2- to 5-fold higher binding efficiency to the latter. Compounds 5 and 6 were also shown to be potent pure AR antagonists. The cell growth studies showed that 5 and 6 inhibit the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells with IC(50) values in the low micromolar range (i.e., <10 microM). Their inhibitory potencies were comparable to that of casodex but remarkably superior to that of flutamide. The pharmacokinetics of compounds 5 and 6 in mice were investigated. Following s.c. administration of 50 mg/kg of 5 and 6, peak plasma levels of 16.82 and 5.15 ng/mL, respectively, occurred after 30 to 60 min, both compounds were cleared rapidly from plasma (terminal half-lives of 44.17 and 39.93 min, respectively), and neither was detectable at 8 h. Remarkably, compound 5 was rapidly converted into a metabolite tentatively identified as 17-(1H-benzimidazol-1-yl)androsta-3-one. When tested in vivo, 5 proved to be very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft, while 6 was ineffective. Compound 5 (50 mg/kg/twice daily) resulted in a 93.8% reduction (P = 0.00065) in the mean final tumor volume compared with controls, and it was also significantly more effective than castration. To our knowledge, this is the first example of an antihormonal agent (an inhibitor of androgen synthesis (CYP17 inhibitor)/antiandrogen) that is significantly more effective than castration in suppression of androgen-dependent prostate tumor growth. In view of these impressive anticancer properties, compound 5 is a strong candidate for development for the treatment of human prostate cancer.
|
Inhibition of [1-beta-3H]-androstenedione binding to human steroid 5-alpha-reductase type I expressed in DU-145 cells at 10 uM
|
Homo sapiens
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model.
Year : 2005
Volume : 48
Issue : 8
First Page : 2972
Last Page : 2984
Authors : Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman D, Farquhar R, Guo Z, Qiu Y, Brodie AM.
Abstract : New chemical entities, steroidal C-17 benzoazoles (5, 6, 9 and 10) and pyrazines (14 and 15) were rationally designed and synthesized. The key reaction for synthesis of the benzoazoles involved the nucleophilic vinylic "addition-elimination" substitution reaction of 3beta-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and benzoazole nucleophiles, while that for synthesis of pyrazines involved palladium-catalyzed cross-coupling reaction of 17-iodoandrosta-5,16-dien-3beta-ol (13) with tributylstannyl diazines. Some of the compounds were shown to be potent inhibitors of human CYP17 enzyme as well as potent antagonist of both wild type and mutant androgen receptors (AR). The most potent CYP17 inhibitors were 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (5, code named VN/124-1), 3beta-hydroxy-17-(5(1)-pyrimidyl)androsta-5,16-diene (15) and 17-(1H-benzimidazole-1-yl)androsta-4,16-dien-3-one (6), with IC(50) values of 300, 500 and 915 nM, respectively. Compounds 5, 6, 14 and 15 were effective at preventing binding of (3)H-R1881 (methyltrienolone, a stable synthetic androgen) to both the mutant LNCaP AR and the wild-type AR, but with a 2.2- to 5-fold higher binding efficiency to the latter. Compounds 5 and 6 were also shown to be potent pure AR antagonists. The cell growth studies showed that 5 and 6 inhibit the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells with IC(50) values in the low micromolar range (i.e., <10 microM). Their inhibitory potencies were comparable to that of casodex but remarkably superior to that of flutamide. The pharmacokinetics of compounds 5 and 6 in mice were investigated. Following s.c. administration of 50 mg/kg of 5 and 6, peak plasma levels of 16.82 and 5.15 ng/mL, respectively, occurred after 30 to 60 min, both compounds were cleared rapidly from plasma (terminal half-lives of 44.17 and 39.93 min, respectively), and neither was detectable at 8 h. Remarkably, compound 5 was rapidly converted into a metabolite tentatively identified as 17-(1H-benzimidazol-1-yl)androsta-3-one. When tested in vivo, 5 proved to be very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft, while 6 was ineffective. Compound 5 (50 mg/kg/twice daily) resulted in a 93.8% reduction (P = 0.00065) in the mean final tumor volume compared with controls, and it was also significantly more effective than castration. To our knowledge, this is the first example of an antihormonal agent (an inhibitor of androgen synthesis (CYP17 inhibitor)/antiandrogen) that is significantly more effective than castration in suppression of androgen-dependent prostate tumor growth. In view of these impressive anticancer properties, compound 5 is a strong candidate for development for the treatment of human prostate cancer.
|
Inhibition of steroid 5-alpha reductase type 1 expressed in HEK 293 cells
|
None
|
453.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of 4'-substituted bicyclic pyridones as non-steroidal inhibitors of steroid 5alpha-reductase.
Year : 2007
Volume : 17
Issue : 13
First Page : 3603
Last Page : 3607
Authors : McCarthy AR, Hartmann RW, Abell AD.
Abstract : 4'-Substituted bicyclic pyridones were prepared and evaluated as non-steroidal inhibitors of type 1 and 2 steroid 5alpha-reductase (SR). A range of 4'-substituents were incorporated into the bicyclic scaffold to investigate SAR within and across different classes of non-steroidal inhibitors of SR. Bicyclic pyridones containing a 4'-benzoyl or long carbon chain tether showed more potent inhibition against type 1 SR than inhibitors with N-substituted acetamide groups in the 4'-position. SAR derived from 4'-substituted bicyclic pyridones reported here do not correlate with SAR derived from known potent 4'-substituted biaryl acid SR inhibitors. A 4'-benzoyl group is favoured by the active site in both isozymes.
|
Inhibition of steroid 5-alpha reductase type 2 expressed in HEK 293 cells
|
None
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of 4'-substituted bicyclic pyridones as non-steroidal inhibitors of steroid 5alpha-reductase.
Year : 2007
Volume : 17
Issue : 13
First Page : 3603
Last Page : 3607
Authors : McCarthy AR, Hartmann RW, Abell AD.
Abstract : 4'-Substituted bicyclic pyridones were prepared and evaluated as non-steroidal inhibitors of type 1 and 2 steroid 5alpha-reductase (SR). A range of 4'-substituents were incorporated into the bicyclic scaffold to investigate SAR within and across different classes of non-steroidal inhibitors of SR. Bicyclic pyridones containing a 4'-benzoyl or long carbon chain tether showed more potent inhibition against type 1 SR than inhibitors with N-substituted acetamide groups in the 4'-position. SAR derived from 4'-substituted bicyclic pyridones reported here do not correlate with SAR derived from known potent 4'-substituted biaryl acid SR inhibitors. A 4'-benzoyl group is favoured by the active site in both isozymes.
|
Inhibition of steroid 5-alpha-reductase activity in Sprague-Dawley rat liver microsomes after 10 mins
|
Rattus norvegicus
|
730.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The anti-androgen effect of ganoderol B isolated from the fruiting body of Ganoderma lucidum.
Year : 2007
Volume : 15
Issue : 14
First Page : 4966
Last Page : 4972
Authors : Liu J, Shimizu K, Konishi F, Kumamoto S, Kondo R.
Abstract : The anti-androgenic activity of the ethanol extract of the fruiting body of Ganoderma lucidum has been previously reported. Ganoderol B with 5alpha-reductase inhibitory activity and the ability to bind to androgen receptor (AR) can inhibit androgen-induced LNCaP cell growth and suppress regrowth of the ventral prostate induced by testosterone in rats. The down-regulation of AR signaling by ganoderol B provides an important mechanism for its anti-androgenic activity. In view of the fact that PSA (prostatic specific antigen, a well-accepted prognostic indicator of prostate cancer) is down-regulated, an important implication of this study is that ganoderol B intervention strategy aimed at toning down the amplitude of androgen signaling could be helpful in controlling morbidity of prostate cancer. In conclusion, our result suggests that ganoderol B might be useful in prostate cancer and benign prostatic hyperplasia (BPH) therapy through suppressing the function of androgen and its receptor.
|
Inhibition of 5-alpha-reductase in rat liver microsome assessed as conversion of [14C] testosterone to [14C] dihydrotestosterone
|
Rattus norvegicus
|
730.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Ganoderic acid DM: anti-androgenic osteoclastogenesis inhibitor.
Year : 2009
Volume : 19
Issue : 8
First Page : 2154
Last Page : 2157
Authors : Liu J, Shiono J, Shimizu K, Kukita A, Kukita T, Kondo R.
Abstract : Prostate cancer is the most common cancer in men in Western countries, with a high incidence of bone metastasis. Ganoderic acid DM, with 5alpha-reductase inhibitory and androgen receptor (AR) binding activity, isolated from the ethanol extracts of Ganoderma lucidum, can inhibit prostate cancer cell growth and block osteoclastogenesis.
|
Inhibition of 5alpha reductase from human prostatic hyperplasia
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Nat. Prod.
Title : Determination of oenothein B as the active 5-alpha-reductase-inhibiting principle of the folk medicine Epilobium parviflorum.
Year : 1996
Volume : 59
Issue : 5
First Page : 490
Last Page : 492
Authors : Lesuisse D, Berjonneau J, Ciot C, Devaux P, Doucet B, Gourvest JF, Khemis B, Lang C, Legrand R, Lowinski M, Maquin P, Parent A, Schoot B, Teutsch G.
Abstract : Several extracts from Epilobium parviflorum, a plant used in Central Europe for the treatment of prostate disorders, were evaluated in a biochemical assay with 5-alpha-reductase. The aqueous extract displaying inhibition of the enzyme was analyzed, the fraction responsible for this activity was purified, and the active compound identified as a macrocyclic tannin, oenothein B (1).
|
Inhibition of human 17beta-HSD7 expressed in HEK293 cells assessed as inhibition of reduction of [14C]estrone into [14C]estradiol at 0.3 uM after 7 hrs
|
Homo sapiens
|
3.7
%
|
|
Journal : J. Med. Chem.
Title : Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.
Year : 2009
Volume : 52
Issue : 23
First Page : 7488
Last Page : 7502
Authors : Bellavance E, Luu-The V, Poirier D.
Abstract : 17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.
|
Inhibition of human 17beta-HSD7 expressed in HEK293 cells assessed as inhibition of reduction of [14C]estrone into [14C]estradiol at 3 uM after 7 hrs
|
Homo sapiens
|
5.4
%
|
|
Journal : J. Med. Chem.
Title : Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.
Year : 2009
Volume : 52
Issue : 23
First Page : 7488
Last Page : 7502
Authors : Bellavance E, Luu-The V, Poirier D.
Abstract : 17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.
|
Inhibition of human prostate 5alpha-reductase type 2 assessed as formation dihydrotestosterone from [4-14C] testosterone
|
Homo sapiens
|
35.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel hybrid from finasteride and epristeride as 5α-reductase inhibitor.
Year : 2011
Volume : 21
Issue : 1
First Page : 475
Last Page : 478
Authors : Yao Z, Xu Y, Zhang M, Jiang S, Nicklaus MC, Liao C.
Abstract : Finasteride and epristeride both inhibit 5α-reductase with high potency via competitive and non-competitive mechanism, respectively. A new hybrid of finasteride and epristeride was designed as a new 5α-reductase inhibitor based on combination principles in medicinal chemistry. Human 5β-reductase was chosen as a plausible surrogate of 5α-reductase type II and the results indicate that although the hybrid compound possesses the main bulk of epristeride, its inhibitory mechanism is same as of finasteride. The hybrid turned out to be a potent 5α-reductase inhibitor in low IC(50) ranges.
|
Inhibition of rat 5-alpha-reductase type 2 by Lineweaver-Burk plot
|
Rattus norvegicus
|
147.49
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and bioactivity of new Finasteride conjugate.
Year : 2011
Volume : 21
Issue : 11
First Page : 3439
Last Page : 3442
Authors : Shuang Z, Jiazhen W, Lijuan Y, Zhuo L, Dahai Y, Jinfeng L, Jing Y, Yongtao L, En-Si W, Xuexun F.
Abstract : Finasteride is a synthetic 4-azasteroid compound that acts by inhibiting type II 5α-reductase, the enzyme that converts the androgen testosterone to 5α-dihydrotestosterone. It was approved by the US FDA for the treatment of benign prostatic hyperplasia and male pattern baldness. Here the acylation product of Finasteride C-18 amide N-polimod was synthesized by employing acylation reaction with polimod amide as a pivotal intermediate. The structure of the key intermediate and target molecule was confirmed by infrared spectrum, (1)H NMR and (13)C NMR spectra and mass spectrum, and the inhibition of the steroid 5α-reductase and the rats' benign prostatic hyperplasia by the new Finasteride conjugate and Finasteride was also determined. The inhibition of the Finasteride conjugate on 5α-reductase was stronger than that of Finasteride. Prostate hyperplasia of rats was reduced by Finasteride conjugate treatment similar to the Finasteride treatment. However, the Finasteride conjugate treated animals showed better viable condition than the Finasteride treated ones, suggesting the new compound may have improved toxicity profile than Finasteride.
|
Inhibition of human type-2 5-alpha reductase expressed in HEK293 cells using [3H]-androstenedione as substrate after 30 mins by HPLC analysis
|
Homo sapiens
|
30.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of novel unsaturated carboxysteroids as human 5α-reductase inhibitors: a legitimate approach.
Year : 2012
Volume : 54
First Page : 728
Last Page : 739
Authors : Aggarwal S, Thareja S, Bhardwaj TR, Haupenthal J, Hartmann RW, Kumar M.
Abstract : In the present study, novel steroidal 17a-substituted 3-cyano-17a-aza-D-homo-3,5-androstadien-17-ones (12-19) and 17a-substituted 17-oxo-17a-aza-D-homo-3,5-androstadien-3-oic acids (20-26) were synthesized from dehydroepiandrosterone acetate (6) along with 17-oxo-19-nor-3,5-androstadien-3-oic acid (30) through a multistep synthesis. Compounds were evaluated for their in vitro 5α-reductase inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity was also determined using rat prostate weighing method. Compounds 21-23 and 25 showed potent inhibition of 5α-reductase II enzyme with IC(50) values of 54.1 ± 9.5, 22.1 ± 2.4, 72.8 ± 2.3 and 26.5 ± 4.4 nM respectively as compared to Finasteride (30.3 nM) along with a significant (p < 0.05) reduction in rat prostate weight.
|
Inhibition of human type-1 5-alpha reductase expressed in HEK293 cells using [3H]-androstenedione as substrate after 30 mins by HPLC analysis
|
Homo sapiens
|
453.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of novel unsaturated carboxysteroids as human 5α-reductase inhibitors: a legitimate approach.
Year : 2012
Volume : 54
First Page : 728
Last Page : 739
Authors : Aggarwal S, Thareja S, Bhardwaj TR, Haupenthal J, Hartmann RW, Kumar M.
Abstract : In the present study, novel steroidal 17a-substituted 3-cyano-17a-aza-D-homo-3,5-androstadien-17-ones (12-19) and 17a-substituted 17-oxo-17a-aza-D-homo-3,5-androstadien-3-oic acids (20-26) were synthesized from dehydroepiandrosterone acetate (6) along with 17-oxo-19-nor-3,5-androstadien-3-oic acid (30) through a multistep synthesis. Compounds were evaluated for their in vitro 5α-reductase inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity was also determined using rat prostate weighing method. Compounds 21-23 and 25 showed potent inhibition of 5α-reductase II enzyme with IC(50) values of 54.1 ± 9.5, 22.1 ± 2.4, 72.8 ± 2.3 and 26.5 ± 4.4 nM respectively as compared to Finasteride (30.3 nM) along with a significant (p < 0.05) reduction in rat prostate weight.
|
Inhibition of testosterone propionate-induced prostate hyperplasia in Wistar rat at 5 mg/kg, ip co-administered with testosterone propionate for 14 days
|
Rattus norvegicus
|
0.0731
%
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition.
Year : 2013
Volume : 69
First Page : 125
Last Page : 138
Authors : Panathur N, Dalimba U, Koushik PV, Alvala M, Yogeeswari P, Sriram D, Kumar V.
Abstract : In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-[4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3-yl]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia.
|
Inhibition of human prostate 5alpha-reductase type 2 assessed as conversion of [3H]testosterone to dihydrotestosterone
|
Homo sapiens
|
8.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Effect of dehydroepiandrosterone derivatives on the activity of 5α-reductase isoenzymes and on cancer cell line PC-3.
Year : 2014
Volume : 22
Issue : 21
First Page : 6233
Last Page : 6241
Authors : Bratoeff E, Garrido M, Ramírez-Apan T, Heuze Y, Sánchez A, Soriano J, Cabeza M.
Abstract : It is well known that testosterone (T) under the influence of 5α-reductase enzyme is converted to dihydrotestosterone (DHT), which causes androgen-dependent diseases. The aim of this study was to synthesize new dehydroepiandrosterone derivatives (3a-e, 4a-i, 6 and 7) having potential inhibitory activity against the 5α-reductase enzyme. This paper also reports the in vivo pharmacological effect of these steroidal molecules. The results from this study showed that all compounds exhibited low inhibitory activity for 5α-reductase type 1 and 2 enzymes and they failed to bind to the androgen receptor. Furthermore, in the in vivo experiment, steroids 3b, 4f, and 4 g showed comparable antiandrogenic activity to that of finasteride; only derivatives 4d and 7 produced a considerable decrease in the weight of the prostate gland of gonadectomized hamsters treated with (T). On the other hand, compounds 4a, f and h showed 100% inhibition of the growth of prostate cancer cell line PC-3, with compound 4 g having a 98.2% antiproliferative effect at 50 μM. The overall data indicated that these steroidal molecules, having an aromatic ester moiety at C-3 (4f-h), could have anticancer properties.
|
Reduction in serum dihydrotestosterone in BPH-induced Sprague-Dawley rat model at 5 mg/kg, po daily for 4 weeks by ELISA
|
Rattus norvegicus
|
50.48
%
|
|
Journal : J. Nat. Prod.
Title : Effects of resveratrol on benign prostatic hyperplasia by the regulation of inflammatory and apoptotic proteins.
Year : 2015
Volume : 78
Issue : 4
First Page : 689
Last Page : 694
Authors : Chung KS, Cheon SY, An HJ.
Abstract : Resveratrol (1) is a natural polyphenolic compound that has cardioprotective, anticancer, and anti-inflammatory properties. Although diverse biological studies of compound 1 have been conducted, no antiproliferative effects of 1 have been reported in benign prostatic hyperplasia (BPH). BPH is a progressive disease related to inflammation and an imbalance in cell growth and apoptosis. The aims of this study were to determine whether 1suppressed BPH progression in rats and to explore the underlying mechanisms related to regulation of inflammation and apoptosis. Compound 1 treatment decreased prostate weight and cell proliferation in this animal model and markedly decreased BPH-related upregulation of iNOS and COX-2 protein expression. In addition, 1 induced Bax expression and suppressed Bcl-2 and Bcl-xL expressions. Furthermore, 1 triggered caspase-3 activation and decreased levels of its substrate, PARP-1. These results suggested that 1 produced an antiproliferative effect by regulating the expression levels of proteins involved in inflammation and apoptosis during BPH.
|
Antiandrogenic activity in female Syrian golden hamsters assessed as inhibition of testosterone propionate-induced flank organ enlargement at 400 ug per animal, topically relative to untreated control
|
Mesocricetus auratus
|
71.0
%
|
|
Journal : MedChemComm
Title : A full conformational characterization of antiandrogen cortexolone-17-propionate and related compounds through theoretical calculations and nuclear magnetic resonance spectroscopy
Year : 2014
Volume : 5
Issue : 7
First Page : 904
Last Page : 914
Authors : Ferraboschi P, Legnani L, Celasco G, Moro L, Ragonesi L, Colombo D
|
In Vitro Inhibition Assay: This work was performed at the MDS Pharma Services, Pharmacology Laboratories, Taiwan. The assay was an in vitro evaluation of the ability of an extract or a pure compound to inhibit the steroid 5alpha -reductase enzyme from metabolizing testosterone into dihydrotestosterone. This is an enzyme-immunoassay (EIA) for quantitative determination of testosterone in human serum or plasma. The significance of this type of inhibition is that it can lead to eradication of benign prostatic hyperplasia (BPH). Two distinct isozymes are found in mice, rats, monkeys and humans: type 1 and II. Each of these isozymes is differentially expressed in tissues and developmental stages. In human, type 1 steroid 5alpha -reductase is predominant in the sebaceous glands of most regions of skin, including scalp and liver and is responsible for approximately one third of circulating DHT. Inhibitors of steroid 5alpha -reductase may be of benefit in the treatment of androgenetic alopecia.
|
Homo sapiens
|
25.0
nM
|
|
Title : Management and treatment of benign prostatic hyperplasia
Year : 2015
|
Inhibition of human prostate type 2 5alpha-reductase assessed as transformation of testosterone to dihydrotestosterone
|
Homo sapiens
|
8.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and activity of novel 16-dehydropregnenolone acetate derivatives as inhibitors of type 1 5α-reductase and on cancer cell line SK-LU-1.
Year : 2015
Volume : 23
Issue : 24
First Page : 7535
Last Page : 7542
Authors : Silva-Ortiz AV, Bratoeff E, Ramírez-Apan T, Heuze Y, Sánchez A, Soriano J, Cabeza M.
Abstract : Testosterone (T) plays a crucial role in prostate growth. In androgen-dependent tissues T is reduced to dihydrotestosterone (DHT) because of the presence of the 5α-reductase enzyme. This androgen is more active than T, since it has a higher affinity for the androgen receptor (AR). When this mechanism is altered, androgen-dependent diseases, including prostate cancer, could result. The aim of this study was to synthesize several 16-dehydropregnenolone acetate derivatives containing a triazole ring at C-21 and a linear or alicyclic ester moiety at C-3 of the steroidal skeleton. These steroids were designed as potential inhibitors of the activity of both types (1 and 2) of 5α-reductase. The cytotoxic activity of these compounds was also evaluated on a panel of PC-3, MCF7, and SK-LU-1 human cancer cell lines. The results from this study showed that with the exception of steroids 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-propionate and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-pentanoate, the compounds exhibit a lower inhibitory activity for both isoenzymes of 5α-reductase than finasteride. Furthermore the 3β-hydroxy-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-20-one and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-acetate derivatives display 80% cytotoxic activity on the SK-LU-1 cell line. These results also indicated that the triazole derivatives, which have a hydroxyl or acetoxy group at C-3, could have an anticancer effect, whereas the derivatives with a alicyclic ester group at C-3 do not show biological activity.
|
Inhibition of human 5alpha-2 reductase expressed in HEK293 cells assessed as suppression of conversion of [3]androstenedione incubated for 30 mins by radioactivity-based HPLC analysis
|
Homo sapiens
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors.
Year : 2016
Volume : 24
Issue : 4
First Page : 779
Last Page : 788
Authors : Aggarwal S, Mahapatra MK, Kumar R, Bhardwaj TR, Hartmann RW, Haupenthal J, Kumar M.
Abstract : In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-D-homo-3,5-androstadien-17-one (26-31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p <0.05) in rat prostate weight. The most potent compound 14 showed 5AR-2 inhibition with IC50 being 15.6nM as compared to clinically used drug finasteride (40nM). There was also a significant inhibition of 5AR-1 with IC50 547nM compared to finasteride (453nM).
|
Inhibition of human 5alpha-1 reductase expressed in HEK293 cells assessed as suppression of conversion of [3]androstenedione incubated for 30 mins by radioactivity-based HPLC analysis
|
Homo sapiens
|
453.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors.
Year : 2016
Volume : 24
Issue : 4
First Page : 779
Last Page : 788
Authors : Aggarwal S, Mahapatra MK, Kumar R, Bhardwaj TR, Hartmann RW, Haupenthal J, Kumar M.
Abstract : In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-D-homo-3,5-androstadien-17-one (26-31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p <0.05) in rat prostate weight. The most potent compound 14 showed 5AR-2 inhibition with IC50 being 15.6nM as compared to clinically used drug finasteride (40nM). There was also a significant inhibition of 5AR-1 with IC50 547nM compared to finasteride (453nM).
|
Inhibition of rat liver 5alpha-reductase using testosterone as substrate incubated for 30 mins measured for 10 mins by fluorescence assay
|
Rattus norvegicus
|
590.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives as dual 5α-reductase inhibitors and androgen receptor antagonists.
Year : 2017
Volume : 27
Issue : 17
First Page : 4212
Last Page : 4217
Authors : Lao K, Sun J, Wang C, Wang Y, You Q, Xiao H, Xiang H.
Abstract : Prostate cancer (PCa) is the second leading cause of death in men. Recently, some researches have showed that 5α-reductase inhibitors were beneficial in PCa treatment as well. In this study, a series of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives have been designed and synthesized in a more simple and convenient method. Most of the synthesized compounds displayed good 5α-reductase inhibitory activities and androgen receptor binding affinities. Their anti-proliferation activities in PC-3 and LNCaP cell lines were also evaluated and the results indicated that most of the synthesized compounds exhibited potent anti-proliferative activities. It is obvious that the androgen-dependent cell line LNCaP was much more sensitive than the androgen-independent cell line PC-3. Among all the synthesized compounds, 11d and 11k displayed the best inhibition activity with 4-fold more sensitive toward LNCaP than PC-3, which was consistent with their high affinities observed in AR binding assay. Molecular modeling studies suggested that 11k could bind to AR in a manner similar to the binding of dihydrotestosterone to AR. Compared to the finasteride, 11k showed a longer plasma half-life (4h) and a better bioavailability. Overall, based on biological activities data, compound 11d and 11k can be identified as potential dual 5α-reductase inhibitors and AR antagonists which might be of therapeutic importance for prostate cancer treatment.
|
Inhibition of rat liver 5alpha-reductase at 50 uM using testosterone as substrate incubated for 30 mins measured for 10 mins by fluorescence assay relative to control
|
Rattus norvegicus
|
94.29
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives as dual 5α-reductase inhibitors and androgen receptor antagonists.
Year : 2017
Volume : 27
Issue : 17
First Page : 4212
Last Page : 4217
Authors : Lao K, Sun J, Wang C, Wang Y, You Q, Xiao H, Xiang H.
Abstract : Prostate cancer (PCa) is the second leading cause of death in men. Recently, some researches have showed that 5α-reductase inhibitors were beneficial in PCa treatment as well. In this study, a series of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives have been designed and synthesized in a more simple and convenient method. Most of the synthesized compounds displayed good 5α-reductase inhibitory activities and androgen receptor binding affinities. Their anti-proliferation activities in PC-3 and LNCaP cell lines were also evaluated and the results indicated that most of the synthesized compounds exhibited potent anti-proliferative activities. It is obvious that the androgen-dependent cell line LNCaP was much more sensitive than the androgen-independent cell line PC-3. Among all the synthesized compounds, 11d and 11k displayed the best inhibition activity with 4-fold more sensitive toward LNCaP than PC-3, which was consistent with their high affinities observed in AR binding assay. Molecular modeling studies suggested that 11k could bind to AR in a manner similar to the binding of dihydrotestosterone to AR. Compared to the finasteride, 11k showed a longer plasma half-life (4h) and a better bioavailability. Overall, based on biological activities data, compound 11d and 11k can be identified as potential dual 5α-reductase inhibitors and AR antagonists which might be of therapeutic importance for prostate cancer treatment.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
-0.3
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-5.85
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
-7.24
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
15.1
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
11.13
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
0.68
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-1.89
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-3.72
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of human type 2 5alpha reductase expressed in HEK293 cells
|
Homo sapiens
|
1.2
nM
|
|
Journal : J Med Chem
Title : Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
Year : 2018
Volume : 61
Issue : 14
First Page : 5822
Last Page : 5880
Authors : Meanwell NA.
Abstract : The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
|
Inhibition of human type 1 5alpha reductase expressed in HEK293 cells
|
Homo sapiens
|
650.0
nM
|
|
Journal : J Med Chem
Title : Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
Year : 2018
Volume : 61
Issue : 14
First Page : 5822
Last Page : 5880
Authors : Meanwell NA.
Abstract : The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
|
Inhibition of human type 1 5alpha reductase
|
Homo sapiens
|
150.0
nM
|
|
Journal : J Med Chem
Title : Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
Year : 2018
Volume : 61
Issue : 14
First Page : 5822
Last Page : 5880
Authors : Meanwell NA.
Abstract : The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
|
Inhibition of human type 2 5alpha reductase
|
Homo sapiens
|
0.18
nM
|
|
Journal : J Med Chem
Title : Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
Year : 2018
Volume : 61
Issue : 14
First Page : 5822
Last Page : 5880
Authors : Meanwell NA.
Abstract : The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
|
Inhibition of type 1 5alpha reductase in human prostate
|
Homo sapiens
|
52.0
nM
|
|
Journal : J Med Chem
Title : Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
Year : 2018
Volume : 61
Issue : 14
First Page : 5822
Last Page : 5880
Authors : Meanwell NA.
Abstract : The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
|
Inhibition of type 2 5alpha reductase in human prostate
|
Homo sapiens
|
58.0
nM
|
|
Journal : J Med Chem
Title : Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
Year : 2018
Volume : 61
Issue : 14
First Page : 5822
Last Page : 5880
Authors : Meanwell NA.
Abstract : The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
|
Inhibition of type 1 5alpha reductase in rat prostate
|
Rattus norvegicus
|
30.0
nM
|
|
Journal : J Med Chem
Title : Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
Year : 2018
Volume : 61
Issue : 14
First Page : 5822
Last Page : 5880
Authors : Meanwell NA.
Abstract : The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
|
Inhibition of type 2 5alpha reductase in rat prostate
|
Rattus norvegicus
|
32.0
nM
|
|
Journal : J Med Chem
Title : Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.
Year : 2018
Volume : 61
Issue : 14
First Page : 5822
Last Page : 5880
Authors : Meanwell NA.
Abstract : The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
6.96
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-63.35
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.04
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.04
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.04
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.04
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of steroid 5-alpha-reductase in human LNCAP cells assessed as reduction in 5- dihydrotestosterone formation incubated for 60 mins by LC-MS analysis
|
Homo sapiens
|
760.0
nM
|
|
Journal : J Nat Prod
Title : Quintaquinone, a Merosesquiterpene from the Yellow Sponge <i>Verongula</i> cf. <i>rigida</i> Esper.
Year : 2020
Volume : 83
Issue : 2
First Page : 532
Last Page : 536
Authors : Jiso A, Kittiwisut S, Chantakul R, Yuenyongsawad S, Putchakarn S, Schäberle TF, Temkitthaworn P, Ingkaninan K, Chaithirayanon K, Plubrukarn A.
Abstract : A chemical investigation of the sponge <i>Verongula</i> cf. <i>rigida</i> led to the isolation of 13 merosesquiterpenes, among which quintaquinone (<b>2</b>), 5-<i>epi</i>-nakijiquinone L (<b>3</b>), and 3-farnesyl-2-hydroxy-5-methoxyquinone (<b>4</b>) were isolated and reported here for the first time. Particularly, compound <b>2</b> is the first member of merosesquiterpenes with a polyketide side chain substituted on C-19. All of the isolated compounds were examined for steroid 5α-reductase inhibitory activity. Cyclospongiaquinone 1 (<b>5</b>) showed a strong activity in the same range as that of standard finasteride.
|
Suppression of prostate tissue weight in Sprague-Dawley rat model of testosterone propionate-induced benign prostatic hyperplasia at 10 mg/kg, po relative to control
|
Rattus norvegicus
|
32.47
%
|
|
Journal : J Nat Prod
Title : Oleanolic Acid Ameliorates Benign Prostatic Hyperplasia by Regulating PCNA-Dependent Cell Cycle Progression <i>In Vivo</i> and <i>In Vitro</i>.
Year : 2020
Volume : 83
Issue : 4
First Page : 1183
Last Page : 1189
Authors : Cheon SY, Jin BR, Kim HJ, An HJ.
Abstract : Oleanolic acid (OA) is a natural, biologically active pentacyclic triterpenoid found in <i>Cornus officinalis</i>. Although <i>C. officinalis</i> and OA have antiproliferative actions, the effects and mechanisms of OA in benign prostatic hyperplasia (BPH) are unclear. We examined the effect of OA in an animal model of testosterone-induced BPH. Male rats were injected with testosterone propionate with or without OA. The inhibitory effect of OA on BPH-1 cells was determined <i>in vitro</i>. Rats with BPH exhibited outstanding BPH symptoms, including prostatic enlargement, upregulated dihydrotestosterone and 5α-reductase 2 levels, and histological changes. Compared with the BPH group, the OA group showed fewer pathological alterations and regular androgen events. OA inhibited prostate cell proliferation by downregulating the expression of proliferating cell nuclear antigen (PCNA) and cell cycle markers in BPH-induced animals. This indicated that OA has superior therapeutic effect in the BPH animal model than finasteride. <i>In vitro</i> studies demonstrated upregulation of PCNA and cell cycle proteins, whereas OA clearly reduced this upregulation. Thus, OA may inhibit the development of BPH by targeting cell cycle progression markers. These suggest that OA is a potential agent for BPH treatment.
|
Antiproliferative activity against androgen-sensitive human LNCAP cells assessed as inhibition of cell growth at 50 uM incubated for 48 hrs by sulforhodamine B assay relative to control
|
Homo sapiens
|
34.6
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of 17β-N-arylcarbamoylandrost-4-en-3-one derivatives and their anti-proliferative effect on human androgen-sensitive LNCaP cell line.
Year : 2016
Volume : 121
First Page : 737
Last Page : 746
Authors : Cortés-Benítez F,Cabeza M,Ramírez-Apan MT,Alvarez-Manrique B,Bratoeff E
Abstract : In this study, we report the synthesis and anti-proliferative effect of a set of eight androst-4-ene-3-one derivatives with different arylcarbamoyl groups at C-17. The novel compounds were prepared from commercially available 3β-hydroxy-5-pregnen-20-one and evaluated against the androgen-sensitive human prostate adenocarcinoma LNCaP cell line. The cancerous cells were exposed to 50 μM of each compound and the proliferating agent testosterone (T) or dihydrotestosterone (DHT). The most potent compounds from this assay were further tested against the androgen-insensitive PC3 cell line. We also demonstrate the activity of these compounds on rat peripheral blood mononuclear cells for comparison. Both 17β-N-[3,5-bis(trifluoromethyl)phenylcarbamoyl]androst-4-ene-3-one (6f) and 17β-N-(1,3-thiazol-2-ylcarbamoyl)androst-4-ene-3-one (6g) exhibited a higher growth inhibitory effect than commercially available drugs finasteride, flutamide and ketoconazole on LNCaP cells in the presence and absence of androgens. In addition, 6f and 6g demonstrated high potency on PC3 cells suggesting an androgen-independent anti-proliferative effect. Moreover, the novel compounds showed a small effect on rat mononuclear cells, an indication of low toxicity.
|
Antiproliferative activity against androgen-sensitive human LNCAP cells assessed as inhibition of testosterone-induced cell growth at 50 uM incubated for 48 hrs by sulforhodamine B assay relative to control
|
Homo sapiens
|
21.1
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of 17β-N-arylcarbamoylandrost-4-en-3-one derivatives and their anti-proliferative effect on human androgen-sensitive LNCaP cell line.
Year : 2016
Volume : 121
First Page : 737
Last Page : 746
Authors : Cortés-Benítez F,Cabeza M,Ramírez-Apan MT,Alvarez-Manrique B,Bratoeff E
Abstract : In this study, we report the synthesis and anti-proliferative effect of a set of eight androst-4-ene-3-one derivatives with different arylcarbamoyl groups at C-17. The novel compounds were prepared from commercially available 3β-hydroxy-5-pregnen-20-one and evaluated against the androgen-sensitive human prostate adenocarcinoma LNCaP cell line. The cancerous cells were exposed to 50 μM of each compound and the proliferating agent testosterone (T) or dihydrotestosterone (DHT). The most potent compounds from this assay were further tested against the androgen-insensitive PC3 cell line. We also demonstrate the activity of these compounds on rat peripheral blood mononuclear cells for comparison. Both 17β-N-[3,5-bis(trifluoromethyl)phenylcarbamoyl]androst-4-ene-3-one (6f) and 17β-N-(1,3-thiazol-2-ylcarbamoyl)androst-4-ene-3-one (6g) exhibited a higher growth inhibitory effect than commercially available drugs finasteride, flutamide and ketoconazole on LNCaP cells in the presence and absence of androgens. In addition, 6f and 6g demonstrated high potency on PC3 cells suggesting an androgen-independent anti-proliferative effect. Moreover, the novel compounds showed a small effect on rat mononuclear cells, an indication of low toxicity.
|
Cytotoxicity against Wistar rat PBMC assessed as inhibition of cell growth at 50 uM incubated for 24 hrs by sulforhodamine B assay relative to control
|
Rattus norvegicus
|
3.7
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of 17β-N-arylcarbamoylandrost-4-en-3-one derivatives and their anti-proliferative effect on human androgen-sensitive LNCaP cell line.
Year : 2016
Volume : 121
First Page : 737
Last Page : 746
Authors : Cortés-Benítez F,Cabeza M,Ramírez-Apan MT,Alvarez-Manrique B,Bratoeff E
Abstract : In this study, we report the synthesis and anti-proliferative effect of a set of eight androst-4-ene-3-one derivatives with different arylcarbamoyl groups at C-17. The novel compounds were prepared from commercially available 3β-hydroxy-5-pregnen-20-one and evaluated against the androgen-sensitive human prostate adenocarcinoma LNCaP cell line. The cancerous cells were exposed to 50 μM of each compound and the proliferating agent testosterone (T) or dihydrotestosterone (DHT). The most potent compounds from this assay were further tested against the androgen-insensitive PC3 cell line. We also demonstrate the activity of these compounds on rat peripheral blood mononuclear cells for comparison. Both 17β-N-[3,5-bis(trifluoromethyl)phenylcarbamoyl]androst-4-ene-3-one (6f) and 17β-N-(1,3-thiazol-2-ylcarbamoyl)androst-4-ene-3-one (6g) exhibited a higher growth inhibitory effect than commercially available drugs finasteride, flutamide and ketoconazole on LNCaP cells in the presence and absence of androgens. In addition, 6f and 6g demonstrated high potency on PC3 cells suggesting an androgen-independent anti-proliferative effect. Moreover, the novel compounds showed a small effect on rat mononuclear cells, an indication of low toxicity.
|
Inhibition of 5-alpha reductase in rat liver microsomes assessed as inhibition of DHT formation using testosterone as substrate incubated for 10 mins by NADPH assay
|
Rattus norvegicus
|
590.1
nM
|
|
Journal : Eur J Med Chem
Title : The one-pot synthesis of butyl-1H-indol-3-alkylcarboxylic acid derivatives in ionic liquid as potent dual-acting agent for management of BPH.
Year : 2020
Volume : 205
First Page : 112616
Last Page : 112616
Authors : Zeng LY,Yang F,Chen K,Zeng Y,Jiang Z,Liu S,Xi B
Abstract : Based on the SAR of both α-AR antagonists and 5α-reductase (5AR) inhibitors, the dual-acting agent 4-(1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indol-3-yl)butanoic acid 4aaa was designed against BPH and synthesized by two steps of N-alkylation. One-pot protocol towards 4aaa was newly developed. With IL [Cmin]Br as solvent, the yield of 4aaa was increased to 75.1% from 16.0% and the reaction time was shortened in 1.5 h from 48 h. 25 derivatives structurally based on arylpiperazine and indolyl butyric acid with alkyl linker were prepared. The protocol was futher extended to get another 14 derivatives wherein O-alkylation was involved, and applied to the synthesis of biologically efficient molecules DPQ and Aripiprazole. Expectedly, compound 4aaa exhibited dual inhibition of α-AR and 5α-reductase, and exhibited no obvious cytotoxicity against human cells. The pharmacokinetic properties of 4aaa was also determined.
|
Inhibition of human recombinant PNMT using AdoMet and DL-norepinephrine hydrocloride as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by fluorescence based analysis relative to control
|
Homo sapiens
|
30.0
%
|
|
