The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Phosphate wie (II), (V) und (VII), Lactone (IX) und Arabinofuranosederivate (X) werden, wie im Formelschema skizziert.

The substrate specificity of dihydrofolate reductase from cells of different origin has been thought to be quite narrow, and unconjugated dihydropterins such as 6-methyl-dihydropterin are known to be very poor substrates. We have reinvestigated the substrate specificity of several dihydropterins and, in addition, have observed that in a new series of unconjugated dihydropterins of the general structure 6-CH2O(CH2)nCH3 several compounds are excellent substrates for the bovine liver enzyme, but none of them bind as well as dihydrofolate. The substrate activity (apparent Vmax) of these compounds increases from 17 to 110% that of the natural substrate, dihydrofolate, as n is increased from 0 to 3. In contrast, these unconjugated dihydropterins are very poor substrates for the Escherichia coli enzyme.

The pathway of KDO biosynthesis and utilization can be described as an essential minor branched pathway in carbohydrate metabolism in Gram-negative bacteria; the pathway is initiated with the key intermediate in the hexose-monophosphate shunt, D-ribulose-5-phosphate. Analogues of D-arabinose-5-phosphate and KDO have been synthesized and tested as possible inhibitors or alternate substrates for D-arabinose-5-phosphate isomerase, KDO-8-phosphate synthase and CMP-KDO synthetase. The substrate analogues synthesized were weak inhibitors of the enzymes involved in KDO biosynthesis. Two intermediates in the biosynthesis of KDO (D-arabinose-5-phosphate and KDO-8-phosphate) have been shown to be weak inhibitors of D-gluconate-6-phosphate dehydrogenase. The specific activities of the enzymes of the KDO pathway (initiating with D-glucose-6-phosphate dehydrogenase and ending with CMP-KDO synthetase) were measured in crude extracts as a function of the specific growth rate and indicate that the level of the individual enzymes are relatively constant. All the specific activities were at least 15 fold greater than the specific activity of CMP-KDO synthetase, suggesting that this may be the rate limiting step in the KDO pathway. Since the specific activities of the individual enzymes involved in the pathway are relatively constant, the overall regulation of carbon flow through the KDO pathway only requires sequential weak end-product inhibition of the enzymes involved to meet the cellular demand for KDO utilized in LPS synthesis.

AbstractDie Kohlenwasserstoffe (I) werden mit Thallium‐tris‐(trifluoracetat) in die Organo‐ Thalliumverbindungen (II) übergeführt, die mit Kaliumfluorid zu den Ary1thallium= (III)‐fluoriden (III) substituiert werden.

AbstractDie Olefine (I) bzw. (III) gehen bei der Umsetzung mit TI(NO3)3 (T TN) in Methanol unter oxidativer Umlagerung in die Carbonylverbindungen (II) (isoliert als 2,4‐Dinitro‐phenylhydrazone in 21‐86% Ausbeute) bzw. (IV) über.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThallium in organic synthesis. XXXII. Oxidative rearrangement of olefins using thallium(III) nitrate (TTN)Alexander. McKillop, John D. Hunt, Frank. Kienzle, Eric. Bigham, and Edward C. TaylorCite this: J. Am. Chem. Soc. 1973, 95, 11, 3635–3640Publication Date (Print):May 1, 1973Publication History Published online1 May 2002Published inissue 1 May 1973https://doi.org/10.1021/ja00792a028RIGHTS & PERMISSIONSArticle Views517Altmetric-Citations60LEARN 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 (753 KB) Get e-Alerts Get e-Alerts