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

E-ring modified steroids as novel potent inhibitors of 17?-hydroxysteroid dehydrogenase type 1
E-ring modified steroids as novel potent inhibitors of 17?-hydroxysteroid dehydrogenase type 1
17?-Hydroxysteroid dehydrogenases (17?-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?-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'-linked 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?-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.
0022-2623
5749-5770
Fischer, D.S.
6bface91-30ed-45ff-a402-f836888b5c90
Allan, G.M.
c2917d25-8637-4fef-9145-88408352154a
Bubert, C.
c7aa7e7e-9dd4-4b95-b0ba-40f82de868d6
Vicker, N.
c3e9714c-ed6a-41e7-ae27-5b433353af7b
Smith, A.
f115f8cb-6c76-444b-ba80-7a1d54276da8
Tutill, H.J.
3303b195-d43a-4e06-bddd-1b1155846904
Purohit, A.
244d02b1-a22c-435e-bbae-8cc97d44c733
Wood, L.
ad6746ad-7b7d-4386-862a-c6ffa94adacb
Packham, G.
fdabe56f-2c58-469c-aadf-38878f233394
Mahon, M.F.
78fc4441-83e9-490d-b0d8-40e20a75d173
Reed, M.J.
dc770ba6-b5fa-4232-b5d9-c7b51569c5d4
Potter, B.V.
0244e337-e9e7-4c24-9750-75b683326c7d
Fischer, D.S.
6bface91-30ed-45ff-a402-f836888b5c90
Allan, G.M.
c2917d25-8637-4fef-9145-88408352154a
Bubert, C.
c7aa7e7e-9dd4-4b95-b0ba-40f82de868d6
Vicker, N.
c3e9714c-ed6a-41e7-ae27-5b433353af7b
Smith, A.
f115f8cb-6c76-444b-ba80-7a1d54276da8
Tutill, H.J.
3303b195-d43a-4e06-bddd-1b1155846904
Purohit, A.
244d02b1-a22c-435e-bbae-8cc97d44c733
Wood, L.
ad6746ad-7b7d-4386-862a-c6ffa94adacb
Packham, G.
fdabe56f-2c58-469c-aadf-38878f233394
Mahon, M.F.
78fc4441-83e9-490d-b0d8-40e20a75d173
Reed, M.J.
dc770ba6-b5fa-4232-b5d9-c7b51569c5d4
Potter, B.V.
0244e337-e9e7-4c24-9750-75b683326c7d

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. (2005) E-ring modified steroids as novel potent inhibitors of 17?-hydroxysteroid dehydrogenase type 1. Journal of Medicinal Chemistry, 48 (18), 5749-5770. (doi:10.1021/jm050348a).

Record type: Article

Abstract

17?-Hydroxysteroid dehydrogenases (17?-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?-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'-linked 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?-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.

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Published date: 2005

Identifiers

Local EPrints ID: 26302
URI: http://eprints.soton.ac.uk/id/eprint/26302
ISSN: 0022-2623
PURE UUID: 0136d0a8-7e53-4d96-b7ef-d0d4a00553a5
ORCID for G. Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 20 Apr 2006
Last modified: 07 Oct 2020 07:02

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