WLB-73502 Dual m-opioid/s1 receptor ligand

As a new approach to potent analgesics for the treatment of chronic pain, we undertook a research program aimed to discover multimodal compounds targeting the s1 receptor (s1R) and the µ-opioid receptor (MOR). The rationale behind it relies on the potentiation of opioid analgesia with s1R antagonists and the efficacy of the later in neuropathic pain, where opioids are poorly effective.

The design and optimization of bispecific drugs is a challenging process, requiring to achieve good affinity for two targets at an appropriate ratio and the right functionality for each of them, while keeping selectivity vs other targets. An additional issue is achieving the optimal drug-like properties required to obtain in vivo activity and adequate pharmacokinetics.

Following a merging approach of MOR and s1R pharmacophores, we designed a new series of dually active 4-aryl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives. Applying a Multiparametric Optimization Approach to deal with hERG blockade and suboptimal selectivity for a1AR in the hit-to-lead phase of the project, we identified the lead compound WLB-72803.1 It showed a balanced dual profile, low hERG inhibition and good ADME properties, as well as a promising in vivo behavior. However, it still showed a suboptimal selectivity profile.

A lead optimization program2 led to identification of the clinical candidate WLB-73502,3 currently in Phase II clinical trials. This compound is highly selective over a panel of 180 targets and shows optimal ADME properties for oral administration. In preclinical models it displays similar nociceptive pain relief, better neuropathic pain relief, improved tolerability, less respiratory depression and less abuse potential than strong opioids, confirming the potential of the dual approach for improving the standard of care in the treatment of pain.

1.García, M. et al. J. Med. Chem, 2020, 63, 2434-2454

2.García, M. et al. J. Med. Chem, 2020, 63, 15508-15526

3.Vidal-Torres, A. et al. Acta Pharmaceutica Sinica B, 2022, doi.org/10.1016/j.apsb.2022.09.018