A medicinal-chemistry-guided approach to selective and druglike sigma 1 ligands.
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.
Corbera
Jordi
J
Department of Medicinal Chemistry, Laboratorios Dr. Esteve S.A. Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain.
Vaño
David
D
Martínez
Daniel
D
Vela
José M
JM
Zamanillo
Daniel
D
Dordal
Alberto
A
Andreu
Francesc
F
Hernandez
Enric
E
Perez
Raquel
R
Escriche
Marisol
M
Salgado
Leonardo
L
Yeste
Sandra
S
Serafini
Maria Teresa
MT
Pascual
Rosalia
R
Alegre
Júlia
J
Calvet
Maria Carme
MC
Cano
Núria
N
Carro
Mónica
M
Buschmann
Helmut
H
Holenz
Jörg
J
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
D008024:Ligands; D017480:Receptors, sigma