A high-throughput screening campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611). Compound 5 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration.

A series of (hetero)arylpyrimidines agonists of the Wnt-β-catenin cellular messaging system have been prepared. These compounds show activity in U2OS cells transfected with Wnt-3a, TCF-luciferase, Dkk-1 and tk-Renilla. Selected compounds show minimal GSK-3β inhibition indicating that the Wnt-β-catenin agonism activity most likely comes from interaction at Wnt-3a/Dkk-1. Two examples 1 and 25 show in vivo osteogenic activity in a mouse calvaria model. One example 1 is shown to activate non-phosphorylated β-catenin formation in bone.

Ovariectomy-induced osteopenia in the rat produces skeletal responses similar to that in a post-menopausal woman. In the ovariectomized (ovx) rat, high bone turnover, and subsequent bone loss, like in the human post-menopausal condition, can be prevented by estrogen replacement. Because of the striking resemblance of skeletal responses in humans and rats in the state of estrogen deficiency, the ovx rat is considered to be a gold standard model for evaluating drugs for prevention and reversal of osteoporosis. This chapter describes the procedure for performing ovariectomy on the rat and the utility of the ovx rat model we have utilized over the last two decades in our laboratory.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCollaborative testing of a manual sodium arsenite method for measurement of nitrogen dioxide in ambient airJohn H. Margeson, Jack C. Suggs, Paul C. Constant Jr., Michael C. Sharp, and George W. ScheilCite this: Environ. Sci. Technol. 1978, 12, 3, 294–297Publication Date (Print):March 1, 1978Publication History Published online1 May 2002Published inissue 1 March 1978https://doi.org/10.1021/es60139a015RIGHTS & PERMISSIONSArticle Views36Altmetric-Citations4LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (492 KB) Get e-Alerts Get e-Alerts