Development of novel azabenzofuran TRPA1 antagonists as in vivo tools

Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists

“…In addition, the potential toxicity of the thiourea moiety prevented its clinical development. The subsequent profiling of 28a performed at Amgen confirmed the high in vivo clearance of the molecule in the rat, associated with poor solubility and very low oral bioavailability (%F = 10) [102].…”

“…Amgen also reported a series of azabenzofuran derivatives (see structure 40 Figure 12) as congeners of Janssen indenones 28a (shown in Figure 7). The introduction of the additional pyridine nitrogen caused a slight loss of potency (compare 40 with 28a) but improved solubility and ameliorated both the PK and the in vivo profile [102].…”

Effect of acyclic monoterpene alcohols and their derivatives on TRP channels

“…In conclusion, we have disclosed here a series of derivatives of the acyclic monoterpene alcohols geraniol, nerol, and citronellol and of the related amines geranylamine and nerylamine that act as potent and selective TRPA1 channel modulators with EC 50 and IC 50 values distinctly lower than those of reference alcohols, compare favourably in terms of potency and/or selectivity with most of other chemotypes presented as TRPA1 modulators and published recently, 22,25 and qualify therefore as useful pharmacological tools in studies on TRP channel modulation using natural products as lead compounds. …”

“…21 Consistent with their interaction with a series of environmental irritants and endogenous mediators of inflammation and pain, TRPA1 channels have been validated as a promising target for various potential therapeutic applications including neuropathic and inflammatory pain and airway disorders. 22 Although a large number of TRPA1 modulators has been already reported, many of them tend to be either reactive or of low potency and/or selectivity and therefore they are not optimal tools for pharmacological studies. The identification of easily synthesized, non-reactive, non-volatile, stable compounds 1d,g,n, 2c,d,h,i,o, 3b,e, as potent and selective TRPA1 modulators should enable further assessment of the TRPA1 pharmacology and designate them as candidates for future evaluation of in vivo efficacy in rodent models of inflammatory and neuropathic pain.…”

TRPA1 as a drug target—promise and challenges

“…3 ). Pharmacokinetic and efficacy data have been described for A-967079 (Abbott), Compound 10 (Amgen), and Compound 31 (Novartis) (Chen et al 2011a ; Copeland et al 2014 ; Rooney et al 2014 ). Compound 10, an azabenzofuran analog, inhibits human and rat TRPA1 with IC 50 of 0.17 and 0.045 μM, respectively, and has favorable PK properties allowing robust unbound plasma exposure (14-fold over rat IC 50 when dosed at 100 mg/kg).…”