Research

E-ring modified steroids as novel potent inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1


Reference:

Fischer, D. S., Allan, G. M., Bubert, C., Vicker, N., Smith, A., Tutill, H. J., Purohit, A., Wood, L., Packham, G., Mahon, M. F., Reed, M. J. and Potter, B. V. L., 2005. E-ring modified steroids as novel potent inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1. Journal of Medicinal Chemistry, 48 (18), pp. 5749-5770.

Related documents:

This repository does not currently have the full-text of this item.
You may be able to access a copy if URLs are provided below.

Official URL:

http://dx.doi.org/10.1021/jm050348a

Abstract

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.

Details

Item Type Articles
CreatorsFischer, D. S., Allan, G. M., Bubert, C., Vicker, N., Smith, A., Tutill, H. J., Purohit, A., Wood, L., Packham, G., Mahon, M. F., Reed, M. J. and Potter, B. V. L.
DOI10.1021/jm050348a
DepartmentsFaculty of Science > Chemistry
RefereedYes
StatusPublished
ID Code4815

Export

Actions (login required)

View Item