Achille Panzeri | Nerviano Medical Sciences fondation (original) (raw)
Papers by Achille Panzeri
Tetrahedron Letters, 1981
ABSTRACT
Journal of Immunoassay, 1994
... a m c/) -2-1 '0 Page 5. TESTOSTERONE SCY-REDUCTASE INHIBITOR 101 at room temperature. ..... more ... a m c/) -2-1 '0 Page 5. TESTOSTERONE SCY-REDUCTASE INHIBITOR 101 at room temperature. ... weighing 60.5 kg, treated with a single oral dose of 0.2 mg of FCE 26073 at the Institute Aster, HGpital Cognacq-Jay, Paris, France. The institutional Ethics Committee ...
Drugs of the Future, 1993
Cheminform, 2010
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Journal of Steroid Biochemistry and Molecular Biology, 1995
FCE 27837 is a novel inhibitor of 5α-reductase, the enzyme responsible for the conversion of test... more FCE 27837 is a novel inhibitor of 5α-reductase, the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compound caused inhibition of human and rat prostatic enzymes, with IC50 values of 51 and 60 nM, respectively. The in vivo effect of FCE 27837 on 5α-reductase was evaluated in adult male rats, treated orally at 10 mg/kg/day for 10 days. The compound caused 33 and 42% reductions in ventral prostate and seminal vesicle weights, respectively. The prostatic content of DHT, measured 6 h after the 10th dose of FCE 27837, was reduced by 75%, whereas T content increased by 442%. Similar effects were observed with 10 mg/kg/day of finasteride, whereas epristeride, tested at the same oral dose, was found to be the least effective compound, decreasing prostate weight by 22% and DHT content by 46%. Castration caused >90% reductions in prostatic weight and prostatic DHT.
Journal of Steroid Biochemistry and Molecular Biology, 1992
A series of 17β-acylurea-4-aza-5α-androstan-3-one derivatives has been assayed in vitro as inhibi... more A series of 17β-acylurea-4-aza-5α-androstan-3-one derivatives has been assayed in vitro as inhibitors of testosterone 5α-reductase, using the particulate fraction of human hyperplastic prostate and rat prostate as enzyme sources. The most active derivatives were 1-[4-methyl-3-oxo-4-aza-5α-androstane-17β-carbonyl]-1,3-dicyclohexylurea (compound 1) and 1-[4-methyl-3-oxo-4-aza-5α-androstane-17β-carbonyl]-1,3-diisopropylurea (compound 3) which demonstrated IC50 values of 41 and 55 nM for the human enzyme and of 83 and 53 nM for the rat enzyme, respectively. Neither compound showed any relevant binding affinity to the rat prostate androgen receptor (IC50 of ≈ 100 and 84 μM). When given orally in immature castrated rats together with subcutaneous testosterone propionate (TP) for 7 consecutive days, compound 3 (laboratory code FCE 26073), at 3 mg/kg/day, significantly decreased the ventral prostate growth promoting effect of TP by 40–50%, whereas compound 1 was ineffective up to the dose of 10 mg/kg/day.
Journal of Steroid Biochemistry and Molecular Biology, 1996
FCE 28260 is a novel inhibitor of 5α-reductase (5αR), the enzyme responsible for the conversion o... more FCE 28260 is a novel inhibitor of 5α-reductase (5αR), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compound caused inhibition of rat and human prostatic enzymes, with IC50 values of 15 and 16 nM, respectively, compared to the values of 30 and 52 nM shown by finasteride. Furthermore, FCE 28260 was highly potent in inhibiting human recombinant 5αR type 2 and 1 isozymes, showing IC50 values of 3.3 and 36 nM, and therefore it was more potent than finasteride (IC50 values of 8.5 and 470 nM) on both isozymes. In prepubertal, T-implanted castrated rats, FCE 28260, given orally for 7 days, reduced ventral prostate growth with an ED50 of 0.8 mg/kg, i.e. five times lower than that shown by finasteride. No anti-androgenic activity in DHT-implanted castrated rats was found up to 10 mg/kg/day. In adult male rats, FCE 28260 reduced prostatic DHT concentrations 6 h after oral dosing with a potency similar to that of finasteride (65% reduction at 1 mg/kg) but was found to be markedly more potent than the reference compound at 24 h (74% reduction in prostate DHT at 10 mg/kg, compared to 26% reduction induced by finasteride). These results indicate that FCE 28260 represents a marked improvement over finasteride.
Journal of Steroid Biochemistry and Molecular Biology, 1993
Turosteride [FCE 26073; 1-(4-methyl-3-oxo-4-aza-5α-androstane-17β-carbonyl)-1,3-diisopropylurea] ... more Turosteride [FCE 26073; 1-(4-methyl-3-oxo-4-aza-5α-androstane-17β-carbonyl)-1,3-diisopropylurea] is a novel inhibitor of 5α-reductase, the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compound caused inhibition of rat and human prostatic enzymes, with IC50 values of 55 and 53 nM, respectively. In addition, turosteride did not show any relevant binding affinity to the rat prostate androgen receptor (IC50 84 μM; relative binding affinity 0.004% of DHT). The endocrine effects of turosteride were evaluated in adult male rats, treated orally at daily doses of 3, 10 and 30mg/kg for 20 days. At these doses, the compound reduced the ventral prostate weight by 10, 33 and 42% and the intraprostatic total DHT content by 61, 74 and 78%, respectively, whereas no change in the intraprostatic content of T was observed. Turosteride caused a 40% reduction of serum DHT levels which, however, did not reach statistical significance, whereas serum T levels were similar to control animals. No effect on serum luteinizing hormone or prolactin was observed. These results indicate that the antiprostatic effect of turosteride in the adult rat is related to inhibition of the conversion of T to DHT. However, at variance with other 5α-reductase inhibitors (e.g. finasteride), turosteride caused a decrease in prostatic DHT not associated with a secondary increase in T content. This peculiarity of turosteride may represent an improvement of the compound over the inhibitors.
Journal of Steroid Biochemistry and Molecular Biology, 1994
Turosteride was tested in a series of studies for its effect on 5α-reductase and for its possible... more Turosteride was tested in a series of studies for its effect on 5α-reductase and for its possible influence on other steroidogenic enzymes and on steroid receptors. The compound was found to inhibit human and rat prostatic 5α-reductases with IC50 values of 55 and 53 nM, respectively, whereas it caused a less marked inhibition of the dog enzyme (IC50 2.2 μM). Turosteride showed no relevant effect on rat adrenal C20,22-desmolase (IC50 254 μM) and human placental aromatase (IC50 > 100 μM), and only at relatively high concentrations it caused inhibition of human placental 5-ene-3β-hydroxysteroid dehydrogenase-isomerase (3β-HSD-I) (IC50 2.5 μM). Turosteride was found to be a selective 5α-reductase inhibitor showing no noteworthy binding to receptors for androgens (relative binding affinity, RBA, 0.004%) estrogens (⩽ 0.005%), progesterone (< 0.005%), glucocorticoids (< 0.01%) and mineralocorticoids (< 0.03%). Its biochemical profile was similar to that of finasteride, whereas 4-MA (17β-N,N-diethyl-carbamoyl-4-methyl-4-aza-5α-androstan-3-one) was confirmed to be a non-selective 5α-reductase inhibitor, showing a degree of binding affinity to the androgen receptor (RBA 0.1%) and a marked inhibition of 3β-HSD-I (IC50 32 nM). When given orally in immature castrated rats together with subcutaneous testosterone propionate (TP) for 7 consecutive days, turosteride reduced the ventral prostate and seminal vesicle growth promoting effect of TP, with IC50 values of ≈ 5 and 6.7 mg/kg/day, whereas levator ani weight was unchanged. In comparison, 4-MA was approx. 3-fold less potent than turosteride in reducing the prostate and seminal vesicle weights and caused a marked reduction of levator ani weight, thus showing its unselectivity.
European Journal of Cancer and Clinical Oncology, 1991
The antitumour activity of the steroidal aromatase inhibitors exemestane (FCE 24304), MDL 18962 a... more The antitumour activity of the steroidal aromatase inhibitors exemestane (FCE 24304), MDL 18962 and atamestane (SH 489) was evaluated on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumours in rats. The compounds were given subcutaneously at daily doses of 10 and 50 mg/kg for 4 weeks. Exemestane was also given orally, at daily doses of 100 and 200 mg/kg. Subcutaneous exemestane induced 30% (10 mg/kg) and 73% (50 mg/kg) regressions of established tumours and strongly reduced the appearance of new tumours. Conversely, atamestane, MDL 18962 and oral exemestane did not affect growth of established tumours nor influenced the appearance of new neoplasms. Aromatase activity of ovarian microsomes (OAA) was reduced by 85%-93% after subcutaneous exemestane and by 25%-59% after MDL 18962, and was unaffected after atamestane. Oral exemestane caused a reduction in OAA of 72%-74%. Serum luteinising hormone (LH) levels were reduced at both the subcutaneous doses of exemestane and at the higher dose of MDL 18962. Atamestane caused an increase in LH levels, while no effect was observed with oral exemestane. The LH-lowering effect of subcutaneous exemestane, the less marked effect of MDL 18962, and the ineffectiveness of oral exemestane were also observed after 10 days of treatment in ovariectomised rats. The antigonadotrophic effect of subcutaneous exemestane, which is probably due to its slight androgenic effect, could contribute to its antitumour activity in the DMBA tumour model in intact rats, through a counteraction of the negative feedback of oestrogens on gonadotropin secretion.
Journal of Steroid Biochemistry and Molecular Biology, 1994
Inhibitors of aromatase and 5α-reductase may be of use for the therapy of postmenopausal breast c... more Inhibitors of aromatase and 5α-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, respectively. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compound was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation () and a similar Ki(inact) (56 vs 66 nM). The compound was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17β-amidic side chains, three compounds, namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5α-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, respectively. When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compounds were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, respectively.
Bioorganic & Medicinal Chemistry, 2014
We report herein the discovery, structure guided design, synthesis and biological evaluation of a... more We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.
Journal of Steroid Biochemistry and Molecular Biology, 1998
PNU 157706 is a novel dual inhibitor of 5α-reductase (5α-R), the enzyme responsible for the conve... more PNU 157706 is a novel dual inhibitor of 5α-reductase (5α-R), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). Tested on a crude preparation of human or rat prostatic 5α-R, PNU 157706 caused enzyme inhibition with ic50 values of 20 and 34 nM, respectively, compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5α-R type I and II isozymes, showing ic50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (ic50 values of 313 and 11.3 nM), particularly on the type I isozyme. PNU 157706 was shown to have no binding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157706 caused a marked and longer lasting reduction of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, respectively). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given orally for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral prostate weight in T- but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than finasteride in reducing prostate weight, the ed50 values being 0.12 and 1.9 mg/kg/day, respectively. These results indicate that PNU 157706 is a promising, potent inhibitor of both type II and I human 5α-R with a very marked antiprostatic effect in the rat.
Tetrahedron Letters, 2009
Tetrahedron Letters, 1997
1. (a). RE Banks, Editor, Organofluorine Chemicals and their Industrial Applications, Ellis Horwo... more 1. (a). RE Banks, Editor, Organofluorine Chemicals and their Industrial Applications, Ellis Horwood Ltd., Chichester (1979). ... 1. (b). R. Filler and Y. Kobayashi, Editors, Biomedicinal Aspects of Fluorine Chemistry, Kodansha Ltd., Tokyo (1982) Elsvier Biomedical Press: Amsterdam .
Journal of Medicinal Chemistry, 2010
Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under co... more Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under control is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDKs) and cyclins (Cy) and inhibiting their activity are regarded as promising antitumor agents to complement the existing therapies. An expansion of pyrazolo[4,3-h]quinazoline chemical class oriented to the development of three points of variability was undertaken leading to a series of compounds able to inhibit CDKs both in vitro and in vivo. Starting from the CDK selective but poorly soluble hit compound 1, we succeeded in obtaining several compounds showing enhanced inhibitory activity both on CDKs and on tumor cells and displaying improved physical properties and pharmacokinetic behavior. Our study led to the identification of compound 59 as a highly potent, orally bioavailable CDK inhibitor that exhibited significant in vivo efficacy on the A2780 ovarian carcinoma xenograft model. The demonstrated mechanisms of action of compound 59 on cancer cell lines and its ability to inhibit tumor growth in vivo render this compound very interesting as potential antineoplastic agent.
Journal of Enzyme Inhibition and Medicinal Chemistry, 1990
Journal of medicinal chemistry, 2009
The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Sta... more The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.
Chemotherapy, 1998
The efficacy of treatment with the 5 alpha-reductase inhibitor PNU 156765 (FCE 28260) was investi... more The efficacy of treatment with the 5 alpha-reductase inhibitor PNU 156765 (FCE 28260) was investigated in the Dunning R3327 prostatic tumor in rats. The compound, given orally at the doses of 10 and 50 mg/kg/day, for 8 weeks, reduced the growth of established tumors by 49-50%, an effect similar to that of flutamide at 5 mg/kg/day (46% inhibition). In a further experiment, the combination of PNU 156765 10 mg/kg/day and flutamide 5 mg/kg/day resulted in greater inhibition than either treatment alone (70 vs. 20% in PNU-156765-treated and 51% in flutamide-treated groups). The effect of the combination was similar to that of castration (75% inhibition). Ventral prostate weight was more markedly reduced by PNU 156765 than by flutamide, and combined treatment was as effective as castration. Prostatic dihydrotestosterone content was markedly reduced by PNU 156765 while prostatic testosterone increased. Concomitant treatment with flutamide antagonized the testosterone increase induced by PNU 156765. These data indicate a role for 5 alpha-reductase inhibitors in the therapy of prostate cancer, in combination with antiandrogens, in order to achieve adequate androgen blockade with minimal side effects.
Tetrahedron Letters, 1981
ABSTRACT
Journal of Immunoassay, 1994
... a m c/) -2-1 '0 Page 5. TESTOSTERONE SCY-REDUCTASE INHIBITOR 101 at room temperature. ..... more ... a m c/) -2-1 '0 Page 5. TESTOSTERONE SCY-REDUCTASE INHIBITOR 101 at room temperature. ... weighing 60.5 kg, treated with a single oral dose of 0.2 mg of FCE 26073 at the Institute Aster, HGpital Cognacq-Jay, Paris, France. The institutional Ethics Committee ...
Drugs of the Future, 1993
Cheminform, 2010
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Journal of Steroid Biochemistry and Molecular Biology, 1995
FCE 27837 is a novel inhibitor of 5α-reductase, the enzyme responsible for the conversion of test... more FCE 27837 is a novel inhibitor of 5α-reductase, the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compound caused inhibition of human and rat prostatic enzymes, with IC50 values of 51 and 60 nM, respectively. The in vivo effect of FCE 27837 on 5α-reductase was evaluated in adult male rats, treated orally at 10 mg/kg/day for 10 days. The compound caused 33 and 42% reductions in ventral prostate and seminal vesicle weights, respectively. The prostatic content of DHT, measured 6 h after the 10th dose of FCE 27837, was reduced by 75%, whereas T content increased by 442%. Similar effects were observed with 10 mg/kg/day of finasteride, whereas epristeride, tested at the same oral dose, was found to be the least effective compound, decreasing prostate weight by 22% and DHT content by 46%. Castration caused >90% reductions in prostatic weight and prostatic DHT.
Journal of Steroid Biochemistry and Molecular Biology, 1992
A series of 17β-acylurea-4-aza-5α-androstan-3-one derivatives has been assayed in vitro as inhibi... more A series of 17β-acylurea-4-aza-5α-androstan-3-one derivatives has been assayed in vitro as inhibitors of testosterone 5α-reductase, using the particulate fraction of human hyperplastic prostate and rat prostate as enzyme sources. The most active derivatives were 1-[4-methyl-3-oxo-4-aza-5α-androstane-17β-carbonyl]-1,3-dicyclohexylurea (compound 1) and 1-[4-methyl-3-oxo-4-aza-5α-androstane-17β-carbonyl]-1,3-diisopropylurea (compound 3) which demonstrated IC50 values of 41 and 55 nM for the human enzyme and of 83 and 53 nM for the rat enzyme, respectively. Neither compound showed any relevant binding affinity to the rat prostate androgen receptor (IC50 of ≈ 100 and 84 μM). When given orally in immature castrated rats together with subcutaneous testosterone propionate (TP) for 7 consecutive days, compound 3 (laboratory code FCE 26073), at 3 mg/kg/day, significantly decreased the ventral prostate growth promoting effect of TP by 40–50%, whereas compound 1 was ineffective up to the dose of 10 mg/kg/day.
Journal of Steroid Biochemistry and Molecular Biology, 1996
FCE 28260 is a novel inhibitor of 5α-reductase (5αR), the enzyme responsible for the conversion o... more FCE 28260 is a novel inhibitor of 5α-reductase (5αR), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compound caused inhibition of rat and human prostatic enzymes, with IC50 values of 15 and 16 nM, respectively, compared to the values of 30 and 52 nM shown by finasteride. Furthermore, FCE 28260 was highly potent in inhibiting human recombinant 5αR type 2 and 1 isozymes, showing IC50 values of 3.3 and 36 nM, and therefore it was more potent than finasteride (IC50 values of 8.5 and 470 nM) on both isozymes. In prepubertal, T-implanted castrated rats, FCE 28260, given orally for 7 days, reduced ventral prostate growth with an ED50 of 0.8 mg/kg, i.e. five times lower than that shown by finasteride. No anti-androgenic activity in DHT-implanted castrated rats was found up to 10 mg/kg/day. In adult male rats, FCE 28260 reduced prostatic DHT concentrations 6 h after oral dosing with a potency similar to that of finasteride (65% reduction at 1 mg/kg) but was found to be markedly more potent than the reference compound at 24 h (74% reduction in prostate DHT at 10 mg/kg, compared to 26% reduction induced by finasteride). These results indicate that FCE 28260 represents a marked improvement over finasteride.
Journal of Steroid Biochemistry and Molecular Biology, 1993
Turosteride [FCE 26073; 1-(4-methyl-3-oxo-4-aza-5α-androstane-17β-carbonyl)-1,3-diisopropylurea] ... more Turosteride [FCE 26073; 1-(4-methyl-3-oxo-4-aza-5α-androstane-17β-carbonyl)-1,3-diisopropylurea] is a novel inhibitor of 5α-reductase, the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). The compound caused inhibition of rat and human prostatic enzymes, with IC50 values of 55 and 53 nM, respectively. In addition, turosteride did not show any relevant binding affinity to the rat prostate androgen receptor (IC50 84 μM; relative binding affinity 0.004% of DHT). The endocrine effects of turosteride were evaluated in adult male rats, treated orally at daily doses of 3, 10 and 30mg/kg for 20 days. At these doses, the compound reduced the ventral prostate weight by 10, 33 and 42% and the intraprostatic total DHT content by 61, 74 and 78%, respectively, whereas no change in the intraprostatic content of T was observed. Turosteride caused a 40% reduction of serum DHT levels which, however, did not reach statistical significance, whereas serum T levels were similar to control animals. No effect on serum luteinizing hormone or prolactin was observed. These results indicate that the antiprostatic effect of turosteride in the adult rat is related to inhibition of the conversion of T to DHT. However, at variance with other 5α-reductase inhibitors (e.g. finasteride), turosteride caused a decrease in prostatic DHT not associated with a secondary increase in T content. This peculiarity of turosteride may represent an improvement of the compound over the inhibitors.
Journal of Steroid Biochemistry and Molecular Biology, 1994
Turosteride was tested in a series of studies for its effect on 5α-reductase and for its possible... more Turosteride was tested in a series of studies for its effect on 5α-reductase and for its possible influence on other steroidogenic enzymes and on steroid receptors. The compound was found to inhibit human and rat prostatic 5α-reductases with IC50 values of 55 and 53 nM, respectively, whereas it caused a less marked inhibition of the dog enzyme (IC50 2.2 μM). Turosteride showed no relevant effect on rat adrenal C20,22-desmolase (IC50 254 μM) and human placental aromatase (IC50 > 100 μM), and only at relatively high concentrations it caused inhibition of human placental 5-ene-3β-hydroxysteroid dehydrogenase-isomerase (3β-HSD-I) (IC50 2.5 μM). Turosteride was found to be a selective 5α-reductase inhibitor showing no noteworthy binding to receptors for androgens (relative binding affinity, RBA, 0.004%) estrogens (⩽ 0.005%), progesterone (< 0.005%), glucocorticoids (< 0.01%) and mineralocorticoids (< 0.03%). Its biochemical profile was similar to that of finasteride, whereas 4-MA (17β-N,N-diethyl-carbamoyl-4-methyl-4-aza-5α-androstan-3-one) was confirmed to be a non-selective 5α-reductase inhibitor, showing a degree of binding affinity to the androgen receptor (RBA 0.1%) and a marked inhibition of 3β-HSD-I (IC50 32 nM). When given orally in immature castrated rats together with subcutaneous testosterone propionate (TP) for 7 consecutive days, turosteride reduced the ventral prostate and seminal vesicle growth promoting effect of TP, with IC50 values of ≈ 5 and 6.7 mg/kg/day, whereas levator ani weight was unchanged. In comparison, 4-MA was approx. 3-fold less potent than turosteride in reducing the prostate and seminal vesicle weights and caused a marked reduction of levator ani weight, thus showing its unselectivity.
European Journal of Cancer and Clinical Oncology, 1991
The antitumour activity of the steroidal aromatase inhibitors exemestane (FCE 24304), MDL 18962 a... more The antitumour activity of the steroidal aromatase inhibitors exemestane (FCE 24304), MDL 18962 and atamestane (SH 489) was evaluated on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumours in rats. The compounds were given subcutaneously at daily doses of 10 and 50 mg/kg for 4 weeks. Exemestane was also given orally, at daily doses of 100 and 200 mg/kg. Subcutaneous exemestane induced 30% (10 mg/kg) and 73% (50 mg/kg) regressions of established tumours and strongly reduced the appearance of new tumours. Conversely, atamestane, MDL 18962 and oral exemestane did not affect growth of established tumours nor influenced the appearance of new neoplasms. Aromatase activity of ovarian microsomes (OAA) was reduced by 85%-93% after subcutaneous exemestane and by 25%-59% after MDL 18962, and was unaffected after atamestane. Oral exemestane caused a reduction in OAA of 72%-74%. Serum luteinising hormone (LH) levels were reduced at both the subcutaneous doses of exemestane and at the higher dose of MDL 18962. Atamestane caused an increase in LH levels, while no effect was observed with oral exemestane. The LH-lowering effect of subcutaneous exemestane, the less marked effect of MDL 18962, and the ineffectiveness of oral exemestane were also observed after 10 days of treatment in ovariectomised rats. The antigonadotrophic effect of subcutaneous exemestane, which is probably due to its slight androgenic effect, could contribute to its antitumour activity in the DMBA tumour model in intact rats, through a counteraction of the negative feedback of oestrogens on gonadotropin secretion.
Journal of Steroid Biochemistry and Molecular Biology, 1994
Inhibitors of aromatase and 5α-reductase may be of use for the therapy of postmenopausal breast c... more Inhibitors of aromatase and 5α-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, respectively. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compound was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation () and a similar Ki(inact) (56 vs 66 nM). The compound was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17β-amidic side chains, three compounds, namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5α-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, respectively. When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compounds were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, respectively.
Bioorganic & Medicinal Chemistry, 2014
We report herein the discovery, structure guided design, synthesis and biological evaluation of a... more We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.
Journal of Steroid Biochemistry and Molecular Biology, 1998
PNU 157706 is a novel dual inhibitor of 5α-reductase (5α-R), the enzyme responsible for the conve... more PNU 157706 is a novel dual inhibitor of 5α-reductase (5α-R), the enzyme responsible for the conversion of testosterone (T) to 5α-dihydrotestosterone (DHT). Tested on a crude preparation of human or rat prostatic 5α-R, PNU 157706 caused enzyme inhibition with ic50 values of 20 and 34 nM, respectively, compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5α-R type I and II isozymes, showing ic50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (ic50 values of 313 and 11.3 nM), particularly on the type I isozyme. PNU 157706 was shown to have no binding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157706 caused a marked and longer lasting reduction of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, respectively). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given orally for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral prostate weight in T- but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than finasteride in reducing prostate weight, the ed50 values being 0.12 and 1.9 mg/kg/day, respectively. These results indicate that PNU 157706 is a promising, potent inhibitor of both type II and I human 5α-R with a very marked antiprostatic effect in the rat.
Tetrahedron Letters, 2009
Tetrahedron Letters, 1997
1. (a). RE Banks, Editor, Organofluorine Chemicals and their Industrial Applications, Ellis Horwo... more 1. (a). RE Banks, Editor, Organofluorine Chemicals and their Industrial Applications, Ellis Horwood Ltd., Chichester (1979). ... 1. (b). R. Filler and Y. Kobayashi, Editors, Biomedicinal Aspects of Fluorine Chemistry, Kodansha Ltd., Tokyo (1982) Elsvier Biomedical Press: Amsterdam .
Journal of Medicinal Chemistry, 2010
Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under co... more Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under control is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDKs) and cyclins (Cy) and inhibiting their activity are regarded as promising antitumor agents to complement the existing therapies. An expansion of pyrazolo[4,3-h]quinazoline chemical class oriented to the development of three points of variability was undertaken leading to a series of compounds able to inhibit CDKs both in vitro and in vivo. Starting from the CDK selective but poorly soluble hit compound 1, we succeeded in obtaining several compounds showing enhanced inhibitory activity both on CDKs and on tumor cells and displaying improved physical properties and pharmacokinetic behavior. Our study led to the identification of compound 59 as a highly potent, orally bioavailable CDK inhibitor that exhibited significant in vivo efficacy on the A2780 ovarian carcinoma xenograft model. The demonstrated mechanisms of action of compound 59 on cancer cell lines and its ability to inhibit tumor growth in vivo render this compound very interesting as potential antineoplastic agent.
Journal of Enzyme Inhibition and Medicinal Chemistry, 1990
Journal of medicinal chemistry, 2009
The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Sta... more The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.
Chemotherapy, 1998
The efficacy of treatment with the 5 alpha-reductase inhibitor PNU 156765 (FCE 28260) was investi... more The efficacy of treatment with the 5 alpha-reductase inhibitor PNU 156765 (FCE 28260) was investigated in the Dunning R3327 prostatic tumor in rats. The compound, given orally at the doses of 10 and 50 mg/kg/day, for 8 weeks, reduced the growth of established tumors by 49-50%, an effect similar to that of flutamide at 5 mg/kg/day (46% inhibition). In a further experiment, the combination of PNU 156765 10 mg/kg/day and flutamide 5 mg/kg/day resulted in greater inhibition than either treatment alone (70 vs. 20% in PNU-156765-treated and 51% in flutamide-treated groups). The effect of the combination was similar to that of castration (75% inhibition). Ventral prostate weight was more markedly reduced by PNU 156765 than by flutamide, and combined treatment was as effective as castration. Prostatic dihydrotestosterone content was markedly reduced by PNU 156765 while prostatic testosterone increased. Concomitant treatment with flutamide antagonized the testosterone increase induced by PNU 156765. These data indicate a role for 5 alpha-reductase inhibitors in the therapy of prostate cancer, in combination with antiandrogens, in order to achieve adequate androgen blockade with minimal side effects.