Design and Discovery of a Selective Small Molecule κ Opioid Antagonist (2-Methyl-N-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242)

Abstract

By use of parallel chemistry coupled with physicochemical property design, a series of selective κ opioid antagonists have been discovered. The parallel chemistry strategy utilized key monomer building blocks to rapidly expand the desired SAR space. The potency and selectivity of the in vitro κ antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure-response relationship between the κ K(i) and the free brain drug levels. This strategy identified 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing and has demonstrated target engagement in healthy volunteers.

Pharmacological Characterization of 2-Methyl-N-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a High-Affinity Antagonist Selective for κ-Opioid Receptors

“…2). These data were similar to those previously obtained for PF-04455242 in the mouse tail-flick assay, where EC 50 values of 0.67 and 12.0 mg/kg were obtained for blockade of KOR-and MOR-mediated effects, respectively (Verhoest et al, 2011). PF-04455242 (32 mg/kg) did not exhibit any agonist activity per se in mice (data not shown).…”

“…The rat tail-flick assay demonstrated that PF-04455242 was systemically active while being devoid of agonist activity in vivo, with a 6.5-fold selectivity for KOR compared with MOR. These data compared well with those obtained for mouse tail flick, with ED 50 values of 0.67 and 12.0 mg/kg for KOR and MOR, respectively (Verhoest et al, 2011). In vivo selectivity of PF-04455242 was also demonstrated using ex vivo and in vivo binding paradigms, with a 4.3-fold selectivity for KOR versus MOR using agonist radioligand binding ex vivo.…”

“…PF-04455242-free drug exposure in plasma was calculated from total plasma (Tp) exposure values using protein binding values (fu,p) determined via equilibrium dialysis (rat fu,p ϭ 0.03; mouse fu,p ϭ 0.122; (Verhoest et al, 2011). and drug molecular weight (372.53) as follows: free drug (nM) ϭ (Tp ϫ 1000 ϫ fu,p)/372.53.…”

“…The presence of PF-04455242 in these plasma samples had no significant effect on the concentration of plasma spiradoline (data not shown). Plasma samples from a mouse tail-flick experiment (Verhoest et al, 2011) were also analyzed for PF-04455242 concentrations. Free plasma PF-04455242 concentrations from mice administered either 0.32, 1, or 3.2 mg/kg PF-04455242 (subcutaneously) were calculated to be 0.644 Ϯ 0.244, 3.28 Ϯ 1.22, and 23.7 Ϯ 13.3 nM, respectively.…”

“…1; Verhoest et al, 2011), for which in vitro and in vivo experiments have been performed to determine its pharmacological and behavioral properties. In addition, with a view to transitioning PF-04455242 to clinical development, receptor occupancy (RO) studies have been used to demonstrate target engagement and establish KOR agonist-induced prolactin challenge as a mechanistic biomarker, both of which can be translated to human studies.…”