Analgesic, anti-inflammatory and joint protective effects of ACD137, a selective negative allosteric modulator of TrkA, in models of chemotherapy-induced peripheral neuropathy and osteoarthritis.

Abstract

OBJECTIVES: The neurotrophin receptor TrkA is a clinically and genetically validated target in pain signaling. Anti-nerve growth factor (NGF) monoclonal antibodies have shown clinical efficacy but with side effects such as rapidly progressing osteoarthritis limiting their use, potentially mediated via inhibition of NGF/p75NTR signaling. Therefore, we sought to identify novel and selective small molecule negative allosteric modulators of tropomyosin receptor kinase A (TrkA) and to verify their analgesic effect. METHODS: We have identified ACD137 as a potent and selective negative allosteric modulator (NAM) of TrkA during a lead optimization program. The potency of ACD137 on TrkA and selectivity over TrkB was determined in cell-based assays. ACD137 was tested for its analgesic and anti-inflammatory effects in a model of chemotherapy induced peripheral neuropathy (CIPN) using paclitaxel and in the mono-iodo acetate (MIA)-induced osteoarthritis model in rats. RESULTS: ACD137 demonstrated an IC-value on TrkA of 1.2 nM and showed approximately 17,300- and 17,600-fold selectivivity for TrkA over TrkB and TrkC, respectively. After oral administration in rats, ACD137 reduced mechanical allodynia in the CIPN model in a dose-dependent manner with maximal analgesic efficacy similar to the effect of gabapentin. In a comparative arthritis study using the anti-NGF antibody tanezumab as comparator, ACD137 reduced both evoked and non-evoked pain behavior as well as inflammation with similar efficacy as tanezumab. Surprisingly, ACD137 demonstrated a significant protective effect against knee joint deterioration, something that was not observed with tanezumab. CONCLUSIONS: The data demonstrates that ACD137 is a potent, selective andactive negative allosteric modulator of TrkA exhibiting analgesic effects in models of neuropathic and nociceptive pain. The molecule possesses promising properties for further pre-clinical development.