- NEUROACTIVE STEROIDS AND METHODS OF PREPARATION
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Disclosed are neuroactive steroid anaesthetic agents, methods for their preparation and compositions comprising the same. The invention provides scaled up and/or GMP methods for preparing neuroactive steroids, such as alfaxalone, alfadolone and alfadolone acetate.
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Paragraph 0097-0101
(2020/01/31)
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- Synthesis of new steroidal inhibitors of P-glycoprotein-mediated multidrug resistance and biological evaluation on K562/R7 erythroleukemia cells
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A simple route for improving the potency of progesterone as a modulator of P-gp-mediated multidrug resistance was established by esterification or etherification of hydroxylated 5α/β-pregnane-3,20-dione or 5β-cholan-3-one precursors. X-ray crystallography of representative 7α-, 11α-, and 17α-(2′R/S)-O-tetrahydropyranyl ether diastereoisomers revealed different combinations of axial-equatorial configurations of the anomeric oxygen. Substantial stimulation of accumulation and chemosensitization was observed on K562/R7 erythroleukemia cells resistant to doxorubicin, especially using 7α,11α-O-disubstituted derivatives of 5α/β-pregnane-3,20-dione, among which the 5β-H-7α-benzoyloxy-11α-(2′R)-O-tetrahydropyranyl ether 22a revealed promising properties (accumulation index 2.9, IC50 0.5 μM versus 1.2 and 10.6 μM for progesterone), slightly overcoming those of verapamil and cyclosporin A. Several 7α,12α-O-disubstituted derivatives of 5β-cholan-3-one proved even more active, especially the 7α-O-methoxymethyl-12α-benzoate 56 (accumulation index 3.8, IC50 0.2 μM). The panel of modulating effects from different O-substitutions at a same position suggests a structural influence of the substituent completing a simple protection against stimulating effects of hydroxyl groups on P-gp-mediated transport.
- De Ravel, Marc Rolland,Alameh, Ghina,Melikian, Maxime,Mahiout, Zahia,Emptoz-Bonneton, Agnès,Matera, Eva-Laure,Lomberget, Thierry,Barret, Roland,Rocheblave, Luc,Walchshofer, Nadia,Beltran, Sonia,El Jawad, Lucienne,Mappus, Elisabeth,Grenot, Catherine,Pugeat, Michel,Dumontet, Charles,Le Borgne, Marc,Cuilleron, Claude Yves
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supporting information
p. 1832 - 1845
(2015/04/21)
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- Allopregnanolone and pregnanolone analogues modified in the C ring: Synthesis and activity
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(25R)-3β-Hydroxy-5α-spirostan-12-one (hecogenin) and 11α-hydroxypregn-4-ene-3,20-dione (11α-hydroxyprogesterone) were used as starting materials for the synthesis of a series of 11- and 12-substituted derivatives of 5ξ-pregnanolone (3α-hydroxy-5α- pregnan-20-one and 3α-hydroxy-5β-pregnan-20-one), the principal neurosteroid acting via γ-aminobutyric acid (GABA). These analogues were designed to study the structural requirements of the corresponding GABA A receptor. Their biological activity was measured by in vitro test with [3H]flunitrazepam as radioligand in which allopregnanolone and its active analogues stimulated the binding to the GABAA receptor. Analysis of the SAR data suggests dependence of the flunitrazepam binding activity on the hydrophobic-hydrophilic balance of the groups at the C-ring edge rather than on specific interactions between them and the receptor.
- Slavíková, Barbora,Bujons, Jordi,Matyá?, Libor,Vidal, Miguel,Babot, Zoila,Kri?tofíková, Zdena,Su?ol, Cristina,Kasal, Alexander
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p. 2323 - 2336
(2013/06/04)
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- Synthesis of deuterium labeled NMDA receptor inhibitor - 20-Oxo-5β-[9,12,12-2H3]pregnan-3α-yl-l- glutamyl 1-ester
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20-Oxo-5β-[9,12,12-2H3]pregnan-3α-yl-l- glutamyl 1-ester 11 was synthesized as an internal standard for quantification of a neuroprotective NMDA receptor ligand, 20-oxo-5β-pregnan-3α-yl-l- glutamyl 1-ester 18 and its metabolites, in
- Kapras, Vojtech,Slavickova, Alena,Stastna, Eva,Vyklicky Jr., Ladislav,Vales, Karel,Chodounska, Hana
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experimental part
p. 282 - 287
(2012/03/26)
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- NEW STEROID INHIBITORS OF PGP FOR USE FOR INHIBITING MULTIDRUG RESISTANCE
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The present invention relates to a compound of formula (I) for its use for reversing or inhibiting multidrug resistance.
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Page/Page column 23
(2011/07/07)
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- Synthesis and GABAA receptor activity of oxygen-bridged neurosteroid analogs
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Three analogs of neuroactive steroids were prepared (4-6) in which 1,11- or 11,19-oxygen bridges give a constrained conformation. Their 3D structures were obtained by ab initio calculations and in the case of 3α-hydroxy-11,19-epoxypregn-4-ene-20-one (4), confirmed by X-ray analysis. Biological activity of the synthetic steroids was assayed in vitro using t-[3H]butylbicycloorthobenzoate as radiolabeled ligand for the GABAA receptor. The activity of compound 4 was similar to that of allopregnanolone (1). 1α,11α-Epoxypregnanolone (6) was more active than pregnanolone (2).
- Alvarez, Lautaro D.,Veleiro, Adriana S.,Baggio, Ricardo F.,Garland, Maria T.,Edelsztein, Valeria C.,Coirini, Hector,Burton, Gerardo
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p. 3831 - 3838
(2008/09/21)
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- Microbial hydroxylation of hydroxyprogesterones and α-glucosidase inhibition activity of their metabolites
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Microbial transformation of 11α-hydroxyprogesterone (1) with Cunninghamella elegans, Gibberella fujikuroi, Fusarium lini, and Candida albicans yielded 11α,15α,16α-trihydroxypregn-4-ene-3,20-dione (3), 11α-hydroxy-5α-pregnane-3,20-dione (4), 6β,11α- dihydroxypregn-4-ene-3,20-dione(5), 11α-hydroxypregna-1,4-diene-3,20-dione (6), 11α,17β-dihydroxyandrost-4-en-3-one (7), and 11α,15α-dihydroxypregn-4-ene-3,20-dione (8). On the other hand, microbial transformation of 17α-hydroxyprogesterone (2) with Cunninghamella elegans and Fusarium Uni yielded 11α,17α- dihydroxypregn-4-ene-3,20-dione (9), and 17α-hydroxypregna-1,4-diene-3,20- dione (10). The structures of the metabolites 3-10 were deduced on the basis of spectroscopic methods. Compound 3 was identified as a new metabolite, which exhibited a promising inhibitory activity against the α-glucosidase enzyme.
- Choudhary, Muhammad Iqbal,Nasir, Muhammad,Khan, Shamsun N.,Atif, Muhammad,Ali, Rahat A.,Khalil, Syed M.,Atta-ur-Rahman
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p. 593 - 599
(2007/10/03)
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