- 2-Amino-1,3-thiazol-4(5H)-ones as potent and selective 11β- hydroxysteroid dehydrogenase type 1 inhibitors: Enzyme-ligand co-crystal structure and demonstration of pharmacodynamic effects in C57Bl/6 mice
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11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has attracted considerable attention during the past few years as a potential target for the treatment of diseases associated with metabolic syndrome. In our ongoing work on 11β-HSD1 inhibitors, a series of new 2-amino-1,3-thiazol-4(5H)-ones were explored. By inserting various cycloalkylamines at the 2-position and alkyl groups or spirocycloalkyl groups at the 5-position of the thiazolone, several potent 11β-HSD1 inhibitors were identified. An X-ray cocrystal structure of human 11β-HSD1 with compound 6d (Ki = 28 nM) revealed a large lipophilic pocket accessible by substitution off the 2-position of the thiazolone. To increase potency, analogues were prepared with larger lipophilic groups at this position. One of these compounds, the 3-noradamantyl analogue 8b, was a potent inhibitor of human 11β-HSD1 (Ki = 3 nM) and also inhibited 11β-HSD1 activity in lean C57Bl/6 mice when evaluated in an ex vivo adipose and liver cortisone to cortisol conversion assay.
- Johansson, Lars,Fotsch, Christopher,Bartberger, Michael D.,Castro, Victor M.,Chen, Michelle,Emery, Maurice,Gustafsson, Sonja,Hale, Clarence,Hickman, Dean,Homan, Evert,Jordan, Steven R.,Komorowski, Renee,Li, Aiwen,McRae, Kenneth,Moniz, George,Matsumoto, Guy,Orihuela, Carlos,Palm, Gunnar,Veniant, Murielle,Wang, Minghan,Williams, Meredith,Zhang, Jiandong
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experimental part
p. 2933 - 2943
(2009/04/10)
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- Synthesis and X-ray studies of chiral allosteric modifiers of hemoglobin
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This study was designed to investigate the effect of chirality on the allosteric activity of a series of Hb allosteric modifiers. The chiral analogues were based on the lead compound (4), JP7, {1-[4-(((3,5-dimethylanilino)carbonyl)methyl)phenoxy]cyclopentanecarboxylic acid} with different D- and L-amino acids conjugated to the JP7 acid moiety. The D-isomers were the most potent in vitro effectors in Hb solutions as well as with whole blood. In general, this study demonstrated that the chirality of extended amino acid side chains in JP7 conjugates plays an important role in observed degree of allosteric activity. The binding site interactions for four analogues were determined by single crystallographic diffraction studies. Conclusions show that the chiral configuration of some of the D-isomers enable the effectors to bind with a greater number of interactions with the protein residues, D- and L-isomers with equivalent or near equivalent allosteric activity did not show any significant differences or interactions between their amino acid side chains and the protein. The most potent effectors, in vitro, were compounds 15 and 19, D-isomers of leucine and phenylalanine, respectively. Compounds 21, 22, 30, and 32 were more potent in vitro in Hb solutions than JP7.
- Youssef, Amal Mamdouh,Safo, Martin K.,Danso-Danquah, Richmond,Joshi, Gajanan S.,Kister, Jean,Marden, Michael C.,Abraham, Donald J.
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p. 1184 - 1195
(2007/10/03)
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- 7 2-(Aminocarbonylalkoxyimino)acetamido! derivatives of cephalosporin
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Cephalosporin antibiotics in which the 7β-acylamido group has the structure STR1 (WHERE R is phenyl, thienyl or furyl; Ra and Rb are each selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, naphthyl, thienyl, furyl, carboxy, C2-5 alkoxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl and cyano, or Ra and Rb together with the carbon atom to which they are attached form a C3-7 cycloalkylidene or cycloalkenylidene group; Rc is hydrogen or C1-4 alkyl; and m and n are each 0 or 1 such that the sum of m and n is 0 or 1) exhibit broad spectrum antibiotic activity characterized by particularly high activity against gram negative microorganisms, including those which produce β-lactamases. The compounds, which are syn isomers or exist as mixtures of syn and anti isomers containing at least 90% of the syn isomer, have particularly good activity against Proteus organisms including indole positive strains and, especially when both Ra and Rb are other than hydrogen, against Pseudomonas organisms.
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