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The in vitro structure-activity relationships of 2 are described. Several of the urea-derived compounds display low-nanomolar binding affinity for CCR2. , Ltd, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan, Fax: +81-55-986-7430 GPR4 was found as an orphan GPCR highly expressed in the lung tissues, and recently reported to be activated by acidification. The activation of GPR4 is thought to lead some inflammatory events such as the production of chemokines and the neutrophils migration to inflammation sites, suggested from our experiments.

1) Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Sagamihara, Kanagawa 229-0195, Japan, Fax: +81-42-685-3714, (2) Teijin Institute for Bio-Medical Research, Tokyo 191-8512, Japan 1alpha,25-Dihydroxyvitamin D3 (1) is the active metabolite of vitamin D3 and plays an important role in calcium and phosphorus homeostasis as well as cellular proliferation and differentiation. It is well established that the vitamin D3 triene structure exists in the thermal "previtamin D/vitamin D" equilibrium through [1,7]-sigmatropic rearrangement in a ratio of 6/94 at 37 oC.

Recent studies in mice have shown that deletion of SFRP-1 leads to decreased osteoblast apoptosis and increased bone formation. The goal of the program was to identify orally available small molecule inhibitors of SFRP-1. Such a drug may be useful for the treatment of bone disorders, including bone resorption disorders such as osteoporosis, and for regulation of bone in humans. Based on an original lead compound in the program (compound 1), a strategy involving the preparation of the corresponding conformationally constrained 6-membered ring analogs (generic structure A) was pursued.

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