130717-61-2Relevant articles and documents
Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor δ agonists
Epple, Robert,Cow, Christopher,Xie, Yongping,Azimioara, Mihai,Russo, Ross,Wang, Xing,Wityak, John,Karanewsky, Donald S.,Tuntland, Tove,Nguyê?-Tran, Van T. B.,Ngo, Cara Cuc,Huang, David,Saez, Enrique,Spalding, Tracy,Gerken, Andrea,Iskandar, Maya,Seidel, H. Martin,Tian, Shin-Shay
experimental part, p. 77 - 105 (2010/04/30)
The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor δ (PPARδ) agonists are reported. The synthesis and structure-activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARδ activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARδ in skeletal muscle.
4, 5-DIARYLTHIAZOLE DERIVATIVES AS CB-1 LIGANDS
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Page/Page column 16, (2010/02/07)
The present invention relates to compounds of formula (I): in which R1 and R2 independently represent phenyl, thienyl or pyridyl and R3represents a group -X-Y-NR4R5 in which X is CO or SO2; Y is absent or represents NH and the other substituente are as defined in the description and their use in the treatment of obesity, psychiatric and neurological disorders and to pharmaceutical compositions containing them.
Antiplatelet Agents Based on Cyclooxygenase Inhibition without Ulcerogenesis. Evaluation and Synthesis of 4,5-Bis(4-methoxyphenyl)-2-substituted-thiazoles
Tanaka, Akito,Sakai, Hiroyoshi,Motoyama, Yukio,Ishikawa, Takatoshi,Takasugi, Hisashi
, p. 1189 - 1199 (2007/10/02)
The syntheses, biological evaluations, and structure-activity relationships of a series of 4,5-bis(4-methoxyphenyl)-2-substituted-thiazoles as potent antiplatelet agents with vasodilatory activity are described. 2-Guanidino-4,5-bis(4-methoxyphenyl)thiazole (3), designed from two parent compounds (itazigrel and timegadine), showed inhibitory activity of malondialdehyde (MDA, IC50 = 31 μM) production which is formed from the cyclooxygenase (CO)-catalyzed oxygenation of arachidonic acid in the synthesis of prostanoids in platelets, with vasodilatory activity (ED50 = 2.0 μM). Further structure-activity relationship studies on 3 culminated in the preparation of 4,5-bis(4-methoxyphenyl)-2-thiazole (10a, FR122047) which exhibited potent inhibitory activity on MDA synthesis in vitro (IC50 = 0.088 μM) and platelet aggregation in guinea pigs ex vivo (100percent inhibition even 6 h after 1.0 mg/kg administration) with vasodilatory activity in vitro (ED50 = 6.2 μM). Moreover, 10a demonstrated no ulcerogenesis effect in rats even at 100 mg/kg dosage (safety margin in rats is more than 70 while that of aspirin is only 1.2) in spite of its potent CO inhibition (IC50 = 0.43 μM), while the use of aspirin, a CO inhibitor and the most popular thromboembolic drug, is restricted by the side effect. Pharmacokinetic studies on 10a have revealed that 10a is detectable in platelet-rich plasma but not in platelet-poor plasma 1 day after oral administration, which indicates that 10a tends to be localized in platelets. This property could be responsible for its low toxicity and reduction of side effects in clinical studies.
