Discovery and Optimization of Highly Potent and Selective AT₂R Antagonists to Relieve Peripheral Neuropathic Pain

Abstract

The angiotensin II type 2 receptor (AT 2 R) has attracted much attention as a potential target for the relief of neuropathic pain, which represents an area of unmet clinical need. A series of 1,2,3,4-tetrahydroisoquinolines with a benzoxazole side-chain were discovered as potent AT 2 R antagonists. Rational optimization resulted in compound 15 , which demonstrated both excellent antagonistic activity against AT 2 R in vitro and analgesic efficacy in a rat chronic constriction injury model. Its favorable physicochemical properties and oral bioavailability make it a promising therapeutic candidate for neuropathic pain.

Nonopioid analgesics discovery and the Valley of Death: EMA401 from concept to clinical trial

“…alleviated mechanical allodynia in the ipsilateral hind paws with a potency similar to that of an orally active 6-cyano-substituted benzoxazole analogue of EMA401 (compound 15) and orally administered pregabalin. 30 The efficacies of single i.p. doses of EMA200 (Smith Laboratory, Australia) and twice-daily i.p.…”

“… 103 In more recent work by others, the nM binding affinity of EMA401 at the AT 2 receptor was confirmed along with the binding affinities of a new series of EMA401 analogues. 30 …”

“…The volume of distribution (V d ) of EMA401 at 3.7 L/kg was an order of magnitude lower than that for EMA200 and EMA300 (Table 3 ), consistent with the fact that EMA401 does not cross the blood–brain barrier. 30 , 52 , 71 The plasma clearance of EMA401 at 1.1 L/h/kg was 9-fold and 6-fold lower than that for EMA200 and EMA300, respectively, and the oral bioavailability of EMA400 and EMA401 was ∼30%, which is acceptable, whereas that for EMA200 and EMA300 at <10% was not (Table 3 ).…”

“… 103 The suitability of EMA401 as the drug candidate for progression to formal development was supported by its good potency, its >10,000-fold binding selectivity over the AT 1 receptor, and its favourable PK. 103 The poor ability of EMA401 to cross the blood–brain barrier 30 , 52 , 103 suggested that central nervous system side effects may be minimal in human clinical trials. In vitro metabolism of EMA401 in hepatocytes from mouse, rat, dog, monkey, and human showed that it had relatively low metabolic stability and that glucuronidation was a major metabolic pathway.…”