AG-041R, a novel indoline-2-one derivative, induces systemic cartilage hyperplasia in rats

AG-041R (3R-1-(2,2-diethoxyethyl)-3-((4 methylphenyl)aminocarbonylmethyl)-3-((4-methylphenyl) ureido)-indoline-2-one) is a novel small compound synthesized as a cholecystokinin-2 (CCK(2))/gastrin receptor antagonist. In the course of the development of this compound, we discovered unexpectedly that oral administration of a high dose for 4 weeks markedly induced systemic cartilage hyperplasia. This change was histologically observed in the auricles, the trachea, the marginal region of the femoral condyle, the xiphoid process and intervertebral disks in rats. Daily intraarticular injections of AG-041R into rat knee joints for 3 weeks also caused cartilage hyperplasia in the marginal region of the femoral condyle, but no hyperplasia was observed in any other cartilage. We have confirmed that chondrogenic activity of AG-041R is an intrinsic property of the compound, and is not due to its CCK(2)/gastrin receptor antagonistic actions. These results indicate that AG-041R is a novel stimulator of chondrogenesis, and can be expected to be a potent therapeutic agent for cartilage disorders.