Two facile methods for preparing 4-fluororesorcinol have been developed. In the first method, the direct fluorination of 1,3-dimethoxybenzene with trifluoromethyl hypofluorite carried out in Freon 11 at −78 °C afforded 2,4-dimethoxyfluorobenzene. Demethylation by heating under reflux in 48% HBr in acetic acid gave 4-fluororesorcinol in an overall yield of 60%. The second method involved the fluorination of 2,6-dimethoxyacetophenone by trifluoromethyl hypofluorite in Freon 11 at −78 °C, leading to 2,6-dimethoxy-3-fluoroacetophenone. On heating under reflux in 48% HBr in acetic acid, 4-fluororesorcinol was obtained in an overall yield of 74%. The latter is the method of choice for preparing 4-fluororesorcinol.

MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards.

A series of quinoline/naphthalene-difluoromethylphosphonates were prepared and were found to be potent PTP1B inhibitors. Most of these compounds bearing polar functionalities or large lipophilic residues did not show appreciable oral bioavailability in rodents while small and less polar analogs displayed moderate to good oral bioavailability. The title compound was found to have the best overall potency and pharmacokinetic profile and was found to be efficacious in animal models of diabetes and cancer.

PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu(119) to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.

ChemInformVolume 36, Issue 18 Natural Products Synthesis of AB and CD Spiroketal of Spongistatin 1 (I). Cheuk Kun Lau, Cheuk Kun Lau Dep. Med. Chem., Merck Frosst Cent. Therap. Res., Kirkland, Que. H9H 3L1, Can.Search for more papers by this authorSimon Crumpler, Simon Crumpler Dep. Med. Chem., Merck Frosst Cent. Therap. Res., Kirkland, Que. H9H 3L1, Can.Search for more papers by this authorKathy Macfarlane, Kathy Macfarlane Dep. Med. Chem., Merck Frosst Cent. Therap. Res., Kirkland, Que. H9H 3L1, Can.Search for more papers by this authorFlorence Lee, Florence Lee Dep. Med. Chem., Merck Frosst Cent. Therap. Res., Kirkland, Que. H9H 3L1, Can.Search for more papers by this authorCarl Berthelette, Carl Berthelette Dep. Med. Chem., Merck Frosst Cent. Therap. Res., Kirkland, Que. H9H 3L1, Can.Search for more papers by this author Cheuk Kun Lau, Cheuk Kun Lau Dep. Med. Chem., Merck Frosst Cent. Therap. Res., Kirkland, Que. H9H 3L1, Can.Search for more papers by this authorSimon Crumpler, Simon Crumpler Dep. Med. Chem., Merck Frosst Cent. Therap. Res., Kirkland, Que. H9H 3L1, Can.Search for more papers by this authorKathy Macfarlane, Kathy Macfarlane Dep. Med. Chem., Merck Frosst Cent. Therap. Res., Kirkland, Que. H9H 3L1, Can.Search for more papers by this authorFlorence Lee, Florence Lee Dep. Med. Chem., Merck Frosst Cent. Therap. Res., Kirkland, Que. H9H 3L1, Can.Search for more papers by this authorCarl Berthelette, Carl Berthelette Dep. Med. Chem., Merck Frosst Cent. Therap. Res., Kirkland, Que. H9H 3L1, Can.Search for more papers by this author First published: 06 April 2005 https://doi.org/10.1002/chin.200518198Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume36, Issue18May 3, 2005 RelatedInformation

The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a β-lactamase assay in CHO-NFAT-bla-Gα16 cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.

AbstractFor Abstract see ChemInform Abstract in Full Text.

AbstractFor Abstract see ChemInform Abstract in Full Text.