title: Synthesis, pharmacological evaluation, and structure-activity relationships of benzopyran derivatives with potent SERM activity.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Chiesi Farmaceutici S.p.A., via Palermo 26/A, I-43100 Parma, Italy. g.amari@chiesigroup.com
authors.forename: Gabriele
authors.initials: G
authors.lastname: Amari
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Armani
authors.forename: Silvia
authors.initials: S
authors.lastname: Ghirardi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Delcanale
authors.forename: Maurizio
authors.initials: M
authors.lastname: Civelli
authors.forename: Paola Lorenza
authors.initials: PL
authors.lastname: Caruso
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Galbiati
authors.forename: Milco
authors.initials: M
authors.lastname: Lipreri
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: 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
chemical_list: D001578:Benzopyrans; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators