The structure--activity relationships of imidazole derivatives as inhibitors of thromboxane (TX) synthetase were investigated. Introduction of various substituents (e.g., one or two methyl groups, a halogen atom, a methylidene group, unsaturated bonds, or a phenylene group) into the alpha position or other positions in the carboxy-bearing side chain of 1-(7-carboxyheptyl)imidazole (15) was found to increase the inhibitory potency. The length of the side chains with the phenylene group was optimum for the inhibitory potency on TX synthetase in the region of 8.5-9.0 A. Among the tested imidazole derivatives, 1-(7-carboxy-7-methyl-2-octynyl)imidazole (47), 4-[3-(1-imidazolyl)-propyl]benzoic acid (50), and (E)-4-(1-imidazolylmethyl)cinnamic acid (54) and its alpha-methyl analogue (57) showed the highest potency with an IC50 in the range of 10(-8) to 10(-9) M. Inhibition by these derivatives was highly selective for the TX synthetase, since other enzymes such as fatty acid cyclo-oxygenase and prostacyclin synthetase were not affected.

BiochemistryStereospecific conversion of prostaglandin D2 to (5Z,13E)-(15S)-9a,-11,,15-trihydroxyprosta-5,13-dien-1-oic acid (9a,l11f-prostaglandin F2) Contributed by Osamu Hayaishi, October 30, 1985 ABSTRACT A prostaglandin F (PGF) synthase was recently purified from bovine lung that catalyzed the reduction of both PGH2 and PGD2 but at different active sites on the enzyme. In view of the recent finding that PGD2 is stereospecifically reduced to a unique biologically active compound, (5Z, 13E)-(15S)-9a,11f3,15-trihydroxyprosta-5,13-dien-l-oic acid (9a,11(-PGF2 or ll-epi-PGF2a), by a human liver cytosolic enzyme, detailed characterization of the products formed from PGH2 and PGD2 by the bovine lung PGF synthase was carried out. Chromatographic characteristics of the products formed and stereochemical analysis procedures using mass spectrometry indicated that the enzyme stereospecifically reduces PGH2 to PGF2a, whereas PGD2 is stereospecifically converted to 9a,11(-PGF2. The finding that this enzyme catalyzes the formation of both C-li hydroxy epimers of PGF2, albeit from different substrates, is of interest in that these two compounds may exert different biological actions.Prostaglandin F2a (PGF2a; also called 9a,lla-PGF2) is produced by a number of mammalian organs (1, 2) and exerts a variety of biological actions (3-6). Three different biosynthetic pathways have been described for the formation of PGF2a: (i) 9,11-endoperoxide reduction of PGH2 (7-9), (ii)

The enzyme thromboxane (TX) synthetase is inhibited by pyridine. The beta-substituted pyridine derivatives showed higher inhibitory potency than the gamma-substituted ones having the same side chain. Among the beta-substituted derivatives containing the omega-carboxyalkyl group, the compounds with 6-8 carbon atoms in the side chain were especially effective. The derivatives holding the phenylene group in the side chain exhibited much higher inhibitory activity than those of the alkylene type. Among them, (E)-3-[4-(3-pyridylmethyl)phenyl]-2-methylacrylic acid hydrochloride (5a) had the highest potency (IC50 = 3 x 10(-9) M). The beta-substituted pyridine derivatives and 1-substituted imidazole derivatives which had the same side chain showed almost the same potency. The beta-substituted pyridine derivatives do not inhibit arachidonic acid cyclooxygenase or prostaglandin I2 synthetase, two other enzymes of the arachidonic cascade.

Der Halbester (I) wird zum Imidazol (II) cyclisiert, aus dem man die Carbonsäure (III) erhält.

A. ABULENCIA et al. This paper describes a measurement of the top quark mass, M top , with the dynamical likelihood method (DLM) using the CDF II detector at the Fermilab Tevatron. The Tevatron produces top/antitop (t t) pairs in p p collisions at a center-of-mass energy of 1.96 TeV. The data sample used in this analysis was accumulated from March 2002 through August 2004, which corresponds to an integrated luminosity of 318 pb ÿ1. We use the t t candidates in the ''lepton ‡ jets'' decay channel, requiring at least one jet identified as a b quark by finding a displaced secondary vertex. The DLM defines a likelihood for each event based on the differential cross section as a function of M top per unit phase space volume of the final partons, multiplied by the transfer functions from jet to parton energies. The method takes into account all possible jet combinations in an event, and the likelihood is multiplied event by event to derive the top quark mass by the maximum likelihood method. Using 63 t t candidates observed in the data, with 9.2 events expected from background, we measure the top quark mass to be 173:2 ‡2:6 ÿ2:4 stat:† 3:2syst:† GeV=c 2 , or 173:2 ‡4:1 ÿ4:0 GeV=c 2 .