The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.

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Abstract. We investigated pharmacological characteristics of the itch-associated response to chronic dermatitis induced by 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone) repeated application in mice. Application of an oxazolone challenge to mice with oxazolone-induced chronic dermatitis evoked severe and transient scratching behavior for up to 1h. Thereafter, mild and continuous scratching behavior was observed for at least 8 h. Both severe and continuous scratching behaviors were suppressed by the opioid-receptor antagonist naltrexone, but not by the H 1 histamine-receptor antagonist fexofenadine, 5-hydroxytryptamine-2 (5-HT 2 )-receptor antagonist methysergide, NK 1 -receptor antagonist LY303870, cyclooxygenase inhibitor indomethacin, or the platelet-activating factor-receptor antagonist YM264. The severe scratching behavior was suppressed by the 5-lipoxygenase inhibitor zileuton and leukotriene B 4 -receptor antagonist ONO-4057, but not by the cysteinyl leukotriene-receptor antagonist montelukast. The continuous scratching behavior was suppressed by pretreatment with the non-selective muscarinic acetylcholine-receptor antagonist atropine and M 3 muscarinic acetylcholine-receptor antagonist darifenacin. These results suggest that leukotriene B 4 receptor and M 3 muscarinic acetylcholine receptor are involved in the itch-associated response induced by repeated application of oxazolone in mice.

Abstract. We investigated the effects of gabapentin and pregabalin on the itch-associated response in a mouse model of chronic dermatitis induced by the repeated application of 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone). Challenging the mice with oxazolone-induced chronic dermatitis with the oxazolone evoked severe and transient scratching behavior until 1 h after the application of oxazolone. Thereafter, a more mild and continuous scratching behavior was also observed for at least 8 h. Both severe and continuous scratching behaviors were suppressed by systemic injection of gabapentin and pregabalin. This effect of these compounds was correlated with its affinity for the α 2 δ subunit of voltage-gated Ca 2+ channels. Intrathecal injection, but not peripheral treatment, with gabapentin inhibited the scratching behavior in this model. Gabapentin failed to suppress the scratching behavior induced by the intradermal injection of compound 48/80 in normal mice. The expression of the α 2 δ-1 subunit in dorsal root ganglion (DRG) from mice following repeated application of oxazolone was significantly higher than that from normal mice. These results suggest that gabapentin and pregabalin show an anti-pruritic activity through α 2 δ-subunit binding, and the up-regulation of the α 2 δ-1 subunit in DRG may therefore play an important role in its anti-pruritic activity.

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