- Structure optimization of a new class of PPARγ antagonists
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Peroxisome proliferator-activated receptor gamma (PPARγ) modulators have found wide application for the treatment of cancers, metabolic disorders and inflammatory diseases. Contrary to PPARγ agonists, PPARγ antagonists have been much less studied and alth
- Hernandez-Olmos, Victor,Knape, Tilo,Heering, Jan,von Knethen, Andreas,Kilu, Whitney,Kaiser, Astrid,Wurglics, Mario,Helmst?dter, Moritz,Merk, Daniel,Schubert-Zsilavecz, Manfred,Parnham, Michael J.,Steinhilber, Dieter,Proschak, Ewgenij
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supporting information
(2019/09/30)
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- CYCLIC AMINES AS BROMODOMAIN INHIBITORS
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The present disclosure relates to compounds, which are useful for inhibition of BET protein function by binding to bromodomains, and their use in therapy.
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Paragraph 0590; 0595
(2014/05/25)
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- Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with ω-carboxyalkoxy or ω-carboxy-1-alkynyl substitution in the side chain
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As part of a search for dihydrofolate reductase (DHFR) inhibitors combining the high potency of piritrexim (PTX) with the high antiparasitic vs mammalian selectivity of trimethoprim (TMP), the heretofore undescribed 2,4-diamino-6-(2′,5′-disubstituted benzyl)pyrido[2,3-d]pyrimidines 6-14 with O-(ω-carboxyalkyl) or ω-carboxy-1-alkynyl groups on the benzyl moiety were synthesized and tested against Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium DHFR vs rat DHFR. Three N-(2,4-diaminopteridin-6-yl)methyl)-2′-(ω-carboxy-1-alkynyl) -dibenz[b,f]azepines (19-21) were also synthesized and tested. The pyridopyrimidine with the best combination of potency and selectivity was 2,4-diamino-5-methyl-6-[2′-(5-carboxy-1-butynyl)-5′-methoxy]benzyl] pyrimidine (13), with an IC50 value of 0.65 nM against P. carinii DHFR, 0.57 nM against M. avium DHFR, and 55 nM against rat DHFR. The potency of 13 against P. carinii DHFR was 20-fold greater than that of PTX (IC50 = 13 nM), and its selectivity index (SI) relative to rat DHFR was 85, whereas PTX was nonselective. The activity of 13 against P. carinii DHFR was 20 000 times greater than that of TMP, with an SI of 96, whereas that of TMP was only 14. However 13 was no more potent than PTX against M. avium DHFR, and its SI was no better than that of TMP. Molecular modeling dynamics studies using compounds 10 and 13 indicated a slight binding preference for the latter, in qualitative agreement with the IC50 data. Among the pteridines, the most potent against P. carinii DHFR and M. avium DHFR was the 2′-(5-carboxy-1-butynyl) dibenz[b,f]azepinyl derivative 20 (IC50 = 2.9 nM), whereas the most selective was the 2′-(5-carboxy-1-pentynyl) analogue 21, with SI values of > 100 against both P. carinii and M. avium DHFR relative to rat DHFR. The final compound, 2,4-diamino-5-[3′-(4-carboxy-1-butynyl)-4′-bromo- 5′-methoxybenzyl]pyrimidine (22), was both potent and selective against M. avium DHFR (IC50 = 0.47 nM, SI = 1300) but was not potent or selective against either P. carinii or T. gondii DHFR.
- Chan, David C. M.,Fu, Hongning,Forsch, Ronald A.,Queener, Sherry F.,Rosowsky, Andre
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p. 4420 - 4431
(2007/10/03)
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- Synthesis of methyl 2-methoxy-5-hydroxycinnamate, a metabolite of Murraya paniculata
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Methyl 2-methoxy-5-hydroxycinnamate 1 has been obtained from 2-hydroxy-5-benzyloxybenzaldehyde 2 in four steps with an overall yield of 26%.
- Padmavathi, Pettela,Kavitha, Jakka,Kanumuri, Raju V.,Subbaraju, Gottumukkala V.
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p. 673 - 674
(2007/10/03)
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- Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(ω-carboxyalkyloxy)benzyl]pyrimidines: Marked improvement in potency relative to trimethoprim and species selectivity relative to piritrexim
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A series of previously undescribed 2,4-diamino-5-[2-methoxy-5-alkoxybenzyl]pyrimidines (3a-e) and 2,4-diamino-5-[2-methoxy-5-(ω-carboxyalkyloxy)benzyl]pyrimidines (3f-k) with up to eight CH2 groups in the alkoxy or ω-carboxyalkyloxy side chain were synthesized and tested for the ability to inhibit partially purified dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat liver in comparison with two standard inhibitors, trimethoprim (1) and piritrexim (2). The latter drug is known to be extremely potent but shows a marked preference for binding to mammalian DHFR, whereas the former is very selective for the parasite enzymes but is a much weaker inhibitor. The underlying strategy for the synthesis of compounds 3a-k was that a hybrid structure embodying some features of both 1 and 2 might possess a more favorable combination of potency and selectivity than either parent drug. The choice of analogues 3f-k was based on the idea that the acidic ω-carboxyl group might interact preferentially with a basic center in the active site of DHFR from any of the parasite species relative to the active site of mammalian DHFR. In addition, the ω-carboxyl group was expected to improve water solubility relative to 1 or 2. In standardized spectrophotometric assays with dihydrofolate as the substrate and NADPH as the cofactor, 2,4-diamino-5-[(2-methoxy-4-carboxybutyloxy)benzyl]pyrimidine (3g) inhibited Pc DHFR with an IC50 of 0.049 μM and rat DHFR with IC50 of 3.9 μM. Its potency against Pc DHFR was 140-fold greater than that of 1 and close to that of 2, and its selectivity index, defined as the ratio IC50(rat liver)/IC50(P. carinii), was 8-fold higher than that of 1 and > 104fold higher than that of 2. Although it was less potent and less selective against Tg than Pc DHFR, it was very potent as well as highly selective against Ma DHFR, with an IC50 of 0.0058 μM and an IC50(rat liver)/IC50(M. avium) ratio of > 600. Because of this favorable combination of potency and selectivity relative to 1 and 2, compound 3g may be viewed as a promising lead in the search for new antifolates with potential clinical activity against P. carinii and other opportunistic pathogens in patients with AIDS.
- Rosowsky,Forsch,Queener
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p. 233 - 241
(2007/10/03)
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- Thyroid Hormone Analogues. Synthesis of 3'-Substituted 3,5-Diiodo-L-thyronines and Quantitative Structure-Activity Studies of in Vivo Thyromimetic Activities in Rat Liver and Heart
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Twenty-nine 3'-substituted derivatives of the thyroid hormone 3,3',5-triiodo-L-thyronine (T3) have been synthesized by using established methods and by new route involving manipulation of a 3'-formyl intermediate.In vitro hormone receptor binding (to intact nuclei) and in vivo thyromimetic activity (induction of mitochondrial 3-phosphoglycerate oxidoreductase, GPDH) were measured in rat liver and heart for these new analogues and for the 18 previously reported 3'-substituted 3,5-diiodo-L-thyronines.Analysis of the binding data using theoretical conformational and quantitative structure-affinity methods implies that the 3'-substituent recognition site on the thyroid hormone receptor is hydrophobic and limited in depth to the length of the natural iodo substituent, but has sufficient width to accomodate a phenyl or cyclohexyl group.Receptor binding is reduced by approximately 10-fold in 3'-acyl derivatives which form strong intramolecular acceptor hydrogen bonds with the ajacent 4'-hydroxyl.The compounds studied showed no differences in their relative affinities for heart and liver nuclei, suggesting that receptors in these tissues are similar.However, the relationships between thyromimetic activity (induction of GPDH) and nuclear binding showed some tissue differences.A high correlation between activity and binding is observed for full agonists in the heart, but an equally significant correlation for the liver data is only seen when 3'-substituent bulk (molar reactivity) is included in the analysis.These results suggest the possibility that differential tissue penetration or access to receptors may occur in vivo.
- Leeson, Paul D.,Ellis, David,Emmett, John C.,Shah, Virendra P.,Showell, Graham A.,Underwood, Anthony H.
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- Pyridyl and pyridazinyl substituted thyronine compounds having selective thyromimetic activity
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This invention relates to chemical compounds which have selective thyromimetic activity. A compound of this invention is 3,5-dibromo-3''-[6-oxo-3(1H)-pyridazinylmethyl]-thyronine.
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