AMG-333

Chemotherapy-induced peripheral neuropathy (CIPN) affects ∼68% of patients undergoing chemotherapy, causing debilitating neuropathic pain and reducing quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing and pain mitigation. Meclizine is an H1 histamine receptor antagonist known to have neuroprotective effects, including an anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN using male and female mice to test agonists of mGluR8 and Group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests, and we imaged Ca²⁺ activity of the large population of dorsal root ganglia (DRG) neurons in vivo For the latter, we used a genetically-encoded Ca²⁺ indicator, Pirt-GCaMP3, which enabled us to monitor different drug interventions at the level of the intact DRG neuronal ensemble. We found that CIPN increased spontaneous Ca²⁺ activity in DRG neurons, increased number of Ca²⁺ transients, and increased hyper-responses to mechanical, thermal, and chemical stimuli. We found that mechanical and thermal pain caused by CIPN was significantly attenuated by the mGluR8 agonist, (S)-3,4-DCPG, the Group II mGluR agonist, LY379268, and the H1 histamine receptor antagonist, meclizine. DRG neuronal Ca²⁺ activity elevated by CIPN was attenuated by LY379268 and meclizine, but not by (S)-3,4-DCPG. Furthermore, meclizine and LY379268 attenuated cisplatin-induced weight loss. These results suggest that Group II mGluR agonist, mGluR8 agonist, and meclizine are promising candidates as new treatment options for CIPN, and studies of their mechanisms are warranted.SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy (CIPN) is a painful condition that affects most chemotherapy patients and persists several months or longer after treatment ends. Research on CIPN mechanism is extensive but has produced only few clinically useful treatments. Using in vivo GCaMP Ca²⁺ imaging in live animals over 1800 neurons/dorsal root ganglia (DRG) at once, we have characterized the effects of the chemotherapeutic drug, cisplatin and three treatments that decrease CIPN pain. Cisplatin increases sensory neuronal Ca²⁺ activity and develops various sensitization. Metabotropic glutamate receptor (mGluR) agonist, LY379268 or the H1 histamine receptor antagonist, meclizine decreases cisplatin's effects on neuronal Ca²⁺ activity and reduces pain hypersensitivity. Our results and experiments provide insights into cellular effects of cisplatin and drugs preventing CIPN pain.

Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.