TY - JOUR
T1 - E-ring modified steroids as novel potent inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1
AU - Fischer, Delphine S.
AU - Allan, Gillian M.
AU - Bubert, Christian
AU - Vicker, Nigel
AU - Smith, Andrew
AU - Tutill, Helena J.
AU - Purohit, Atul
AU - Wood, Lynn
AU - Packham, Graham
AU - Mahon, Mary F.
AU - Reed, Michael J.
AU - Potter, Barry V. L.
PY - 2005
Y1 - 2005
N2 - 17 beta-Hydroxysteroid dehydrogenases (17 beta-HSDs) are an important class of steroidogenic enzymes that regulate the bioavailability of active estrogens and androgens and are as yet a relatively unexploited therapeutic target. Based on our investigations and those of others, E-ring modified steroids were identified as a useful template for the design of inhibitors of 17 beta-HSD type 1, an enzyme involved in the conversion of estrone into estradiol. The synthesis and biological evaluation of a new series of N- and C-substituted 1,3,5(10)-estratrien-[17,16-c]pyrazoles and the corresponding SAR are discussed. Among the N-alkylated analogues, the most potent inhibitor was the 1'-methoxyethyl derivative, 41, with an IC50 of 530 nM in T47-D human breast cancer cells. The X-ray crystal structure of the 1'-isobutyl derivative, 37, was determined. Further optimization of the template using parallel synthesis resulted in a library of C5'-Iinked amides from which 73 emerged. This pyridylethyl amide had an IC50 of 300 nM and its activity, with that of 41, suggests the importance of hydrogen bond acceptor groups in the pyrazole side chain. Both 41 and 73 displayed selectivity over 17 beta-HSD type 2, and preliminary investigations showed 41 to be nonestrogenic in vitro in a luciferase reporter gene assay in contrast to the parent pyrazole 25. Molecular modeling studies, which support these findings, and a QSAR, the predictive power of which was demonstrated, are also presented.
AB - 17 beta-Hydroxysteroid dehydrogenases (17 beta-HSDs) are an important class of steroidogenic enzymes that regulate the bioavailability of active estrogens and androgens and are as yet a relatively unexploited therapeutic target. Based on our investigations and those of others, E-ring modified steroids were identified as a useful template for the design of inhibitors of 17 beta-HSD type 1, an enzyme involved in the conversion of estrone into estradiol. The synthesis and biological evaluation of a new series of N- and C-substituted 1,3,5(10)-estratrien-[17,16-c]pyrazoles and the corresponding SAR are discussed. Among the N-alkylated analogues, the most potent inhibitor was the 1'-methoxyethyl derivative, 41, with an IC50 of 530 nM in T47-D human breast cancer cells. The X-ray crystal structure of the 1'-isobutyl derivative, 37, was determined. Further optimization of the template using parallel synthesis resulted in a library of C5'-Iinked amides from which 73 emerged. This pyridylethyl amide had an IC50 of 300 nM and its activity, with that of 41, suggests the importance of hydrogen bond acceptor groups in the pyrazole side chain. Both 41 and 73 displayed selectivity over 17 beta-HSD type 2, and preliminary investigations showed 41 to be nonestrogenic in vitro in a luciferase reporter gene assay in contrast to the parent pyrazole 25. Molecular modeling studies, which support these findings, and a QSAR, the predictive power of which was demonstrated, are also presented.
UR - http://dx.doi.org/10.1021/jm050348a
U2 - 10.1021/jm050348a
DO - 10.1021/jm050348a
M3 - Article
SN - 0022-2623
VL - 48
SP - 5749
EP - 5770
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 18
ER -