Orally available, selective, high-affinity type-2 angiotensin II receptor (AT2R) antagonist with in vivo pain relief efficacy.
EMA401, the (3S)-enantiomer of EMA400 (PD-126,055), is a selective, high-affinity type-2 angiotensin II receptor (AT2R) antagonist (IC50 = 39.5 nM/>39 μM against 50 pM CGP 42112A for binding human AT2R/AT1R; IC50 = 39.5 nM/408 μM against 40 nM Ang II for binding r at AT2R/AT1R). EMA401, but not the AT1R antagonist losartan, is shown to inhibit capsaicin (200 nM) responses in cultured neurons of human and r at DRG (IC50 = 10 nM). EMA401 is orally available (F = 33.2%, t1/2 = 5.7 h, Cmax = 885 ng/mL post 10 mg/kg oral dosage in rats) and exhibits in vivo pain relief efficacy among adult male SD rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve (ED50 = 10 μg/kg via i.p. using the racemate EMA400).
