Novel structural templates for estrogen-receptor ligands and prospects for combinatorial synthesis of estrogens.
BACKGROUND
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 close 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.
Fink
B E
BE
Department of Chemistry, University of Illinois, 600 S. Mathews Avenue,Urbana, IL 61801, USA.
Mortensen
D S
DS
Stauffer
S R
SR
Aron
Z D
ZD
Katzenellenbogen
J A
JA
D001665:Binding Sites; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020849:Raloxifene Hydrochloride; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000378:metabolism; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014961:X-Ray Diffraction
D004965:Estrogen Antagonists; D004967:Estrogens; D007093:Imidazoles; D007555:Isoxazoles; D008024:Ligands; D010080:Oxazoles; D010880:Piperidines; D011720:Pyrazoles; D011960:Receptors, Estrogen; D013844:Thiazoles; D020849:Raloxifene Hydrochloride; D004958:Estradiol