title: A medicinal-chemistry-guided approach to selective and druglike sigma 1 ligands.
abstract: Based on a medicinal-chemistry-guided approach, three novel series of druglike cycloalkyl-annelated pyrazoles were synthesized and display high affinity (pKi>8) for the sigma1 receptor. Structure-affinity relationships were established, and the different scaffolds were optimized with respect to sigma1 binding and selectivity versus the sigma2 receptor and the hERG channel, resulting in selective compounds that have Ki values (for sigma1) in the subnanomolar range. Selected compounds were screened for cytochrome P450 inhibition (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4), metabolic stability (rat and human liver microsomes), and cell-membrane permeability (Caco-2). They showed favorable in vitro ADME properties as well as favorable calculated druglike and experimental physicochemical properties. Furthermore, compounds 7 f and 17 a, for example, displayed high selectivity (affinity) for the sigma1 receptor against a wide range of other receptors (>60). With these valuable tool compounds in hand, we are further exploring the role of the sigma1 receptor in relevant animal models corresponding to such medicinal indications as drug abuse, pain, depression, anxiety, and psychosis.
authors.affiliation: Department of Medicinal Chemistry, Laboratorios Dr. Esteve S.A. Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Corbera
authors.forename: David
authors.initials: D
authors.lastname: Vaño
authors.forename: Daniel
authors.initials: D
authors.lastname: Martínez
authors.forename: José M
authors.initials: JM
authors.lastname: Vela
authors.forename: Daniel
authors.initials: D
authors.lastname: Zamanillo
authors.forename: Alberto
authors.initials: A
authors.lastname: Dordal
authors.forename: Francesc
authors.initials: F
authors.lastname: Andreu
authors.forename: Enric
authors.initials: E
authors.lastname: Hernandez
authors.forename: Raquel
authors.initials: R
authors.lastname: Perez
authors.forename: Marisol
authors.initials: M
authors.lastname: Escriche
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salgado
authors.forename: Sandra
authors.initials: S
authors.lastname: Yeste
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Serafini
authors.forename: Rosalia
authors.initials: R
authors.lastname: Pascual
authors.forename: Júlia
authors.initials: J
authors.lastname: Alegre
authors.forename: Maria Carme
authors.initials: MC
authors.lastname: Calvet
authors.forename: Núria
authors.initials: N
authors.lastname: Cano
authors.forename: Mónica
authors.initials: M
authors.lastname: Carro
authors.forename: Helmut
authors.initials: H
authors.lastname: Buschmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Holenz
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D017480:Receptors, sigma