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 σ1 receptor. Structure-affinity relationships were established, and the different scaffolds were optimized with respect to σ1 binding and selectivity versus the σ2 receptor and the hERG channel, resulting in selective compounds that have Ki values (for σ1) 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 σ1 receptor against a wide range of other receptors (> 60). With these valuable tool compounds in hand, we are further exploring the role of the σ1 receptor in relevant animal models corresponding to such medicinal indications as drug abuse, pain, depression, anxiety, and psychosis. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.