Synthesis, pharmacological evaluation, and structure-activity relationships of benzopyran derivatives with potent SERM activity.
The synthesis, binding affinity for estrogen receptor subtypes (ER alpha and ER beta) and pharmacological activity on rat uterus of a new class of potent ligands, characterized by a 3-phenylbenzopyran scaffold with a basic side chain in position 4, are reported. Some of these compounds, endowed with very high receptor affinity, showed potent inhibition of agonist-stimulated uterine growth, with no or limited proliferative effect. Binding affinity mostly depended on the nature and position of substituents at the 3-phenyl ring, while the uterine activity seems to be affected by basic chain length. Compound 9c (CHF4227) showed excellent binding affinity and antagonist activity on the uterus. The docking of benzopyran derivatives explained the structure-affinity relationships observed for 3-phenyl substitution: a small, hydrophobic 4'-substituent could interact with a small accessory binding cavity, while di-substitution at 4' and 3' led to some ER alpha selectivity. This selectivity can be ascribed to differences in amino acid composition and side chain conformation in the region accommodating the 3-phenyl ring at human ER alpha and ER beta ligand-binding domain.
Amari
Gabriele
G
Department of Medicinal Chemistry, Chiesi Farmaceutici S.p.A., via Palermo 26/A, I-43100 Parma, Italy. g.amari@chiesigroup.com
Armani
Elisabetta
E
Ghirardi
Silvia
S
Delcanale
Maurizio
M
Civelli
Maurizio
M
Caruso
Paola Lorenza
PL
Galbiati
Elisabetta
E
Lipreri
Milco
M
Rivara
Silvia
S
Lodola
Alessio
A
Mor
Marco
M
D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators