TY - JOUR
T1 - Novel structural templates for estrogen-receptor ligands and prospects for combinatorial synthesis of estrogens
AU - Fink, Brian E.
AU - Mortensen, Deborah S.
AU - Stauffer, Shaun R.
AU - Aron, Zachary D.
AU - Katzenellenbogen, John A.
N1 - We are grateful for support of this research through grants from the National Institutes of Health (PHS 5R37 DKI 5556) and the U.S. Amly Breast Cancer Research Program (DAMDl7-97-l-7076). We thank Kathryn Carlson for determining estrogen receptor binding affinities. NMR spectra were obtained in the Varian Oxford Instrument Center for Excellence in NMR Laboratory. Funding for this instrumentation was provided in part from the W.M. Keck Foundation, the National Institutes of Health (PHS 1 SlO RR104444-01) and the National Science Foundation (NSF CHE 96-10502). Mass spectra were obtained instruments supported by grants from the National Institute of General Sciences (GM 27029), the National Institutes of Heath (RR 01575), the National Science Foundation (PCM 8121494).
PY - 1999/4
Y1 - 1999/4
N2 - Introduction: The development of estrogen pharmaceutical agents with appropriate tissue-selectivity profiles has not yet benefited substantially from the application of combinatorial synthetic approaches to the preparation of structural classes that are known to be ligands for the estrogen receptor (ER). We have developed an estrogen pharmacophore that consists of a simple heterocyclic core scaffold, amenable to construction by combinatorial methods, onto which are appended 3-4 peripheral substituents that embody substructural motifs commonly found in nonsteroidal estrogens. The issue addressed here is whether these heterocyclic core structures can be used to prepare ligands with good affinity for the ER. Results: We prepared representative members of various azole core structures. Although members of the imidazole, thiazole or isoxazole classes generally have weak binding for the ER, several members of the pyrazole class show good binding affinity. The high-affinity pyrazoles bear dose conformational relationship to the nonsteroidal ligand raloxifene, and they can be fitted into the ligand-binding pocket of the ER-raloxifene X-ray structure. Conclusions: Compounds such as these pyrazoles, which are novel ER ligands, are well suited for combinatorial synthesis using solid-phase methods.
AB - Introduction: The development of estrogen pharmaceutical agents with appropriate tissue-selectivity profiles has not yet benefited substantially from the application of combinatorial synthetic approaches to the preparation of structural classes that are known to be ligands for the estrogen receptor (ER). We have developed an estrogen pharmacophore that consists of a simple heterocyclic core scaffold, amenable to construction by combinatorial methods, onto which are appended 3-4 peripheral substituents that embody substructural motifs commonly found in nonsteroidal estrogens. The issue addressed here is whether these heterocyclic core structures can be used to prepare ligands with good affinity for the ER. Results: We prepared representative members of various azole core structures. Although members of the imidazole, thiazole or isoxazole classes generally have weak binding for the ER, several members of the pyrazole class show good binding affinity. The high-affinity pyrazoles bear dose conformational relationship to the nonsteroidal ligand raloxifene, and they can be fitted into the ligand-binding pocket of the ER-raloxifene X-ray structure. Conclusions: Compounds such as these pyrazoles, which are novel ER ligands, are well suited for combinatorial synthesis using solid-phase methods.
KW - Arylpyrazoles
KW - Combinatorial chemistry
KW - Estrogen ligands
KW - Estrogen receptor
KW - Nonsteroidal estrogens
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U2 - 10.1016/S1074-5521(99)80037-4
DO - 10.1016/S1074-5521(99)80037-4
M3 - Article
AN - SCOPUS:0033117680
SN - 1074-5521
VL - 6
SP - 205
EP - 219
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 4
ER -