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Homologues of idoxifene: variation of estrogen receptor binding and calmodulin antagonism with chain length

Lookup NU author(s): Dr Ian HardcastleORCiD

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Abstract

A series of homologs of idoxifene [1a, (E)-1-[4-(N-pyrrolidinoethoxy)phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene] and selected homologs of 4-iodotamoxifen [2a, (E)-1-[4-[(N-dimethylamino)ethoxy]phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene] with the side chain (CH₂)_n varying in length from n = 3 (1b, 2b) to n = 10 (1i, 2i) have been synthesized and tested for antagonism of the calmodulin-dependent activity of cAMP phosphodiesterase and for binding affinity to rat uterine estrogen receptor. Compared with 1a (IC₅₀ = 1.5 μM), the homologs showed a progressive increase in calmodulin antagonism with a maximum inhibition at n = 7−9 (1f−h) (IC₅₀ = 0.2 μM), declining at n = 10 (1i) to IC₅₀ = 1.6 μM. In the pyrrolidino series, estrogen receptor binding affinity peaked at n = 3 (1b, RBA = 23; estradiol = 100), declining by n = 10 (1i) to RBA = 0.4, but the homolog n = 8 (1g, RBA = 3.5) was still comparable to tamoxifen (RBA = 3.9). A similar pattern of activity was seen for the dimethylamino counterparts. These compounds represent a new class of antiestrogens with potent calmodulin antagonism.

Publication metadata

Author(s): Hardcastle IR, Rowlands MG, Grimshaw RM, Houghton J, Jarman M

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 1996

Volume: 39

Issue: 4

Pages: 999-1004

Print publication date: 16/10/1996

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society

URL: http://dx.doi.org/10.1021/jm9505472

DOI: 10.1021/jm9505472

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