5454-38-6Relevant academic research and scientific papers
Substituted heterocyclic thiourea compounds as a new class of anti-allergic agents inhibiting IgE/FcεRI receptor mediated mast cell leukotriene release
Venkatachalam,Qazi,Samuel,Uckun
, p. 1095 - 1105 (2007/10/03)
Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of allergy and asthma. We synthesized various analogues of indolyl, naphthyl and phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and examined their in vitro effects on the high affinity IgE receptor/FcεRI-mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea compounds tested, there were 7 active compounds and N-[1-(1-naphthyl)ethyl]-N′-[2-(ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC50=0.002 μM) and N-[1-(1R)-naphthylethyl]-N′-[2-(5-methylpyridyl)]thiourea (compound 5) (IC50=0.005 μM) were identified as the lead compounds. Among the 11 indolylethyl thiourea compounds tested, there were seven active compounds and the halopyridyl compounds N-[2-(3-indolylethyl)]-N′-[2-(5-chloropyridyl)]thiourea (24) and N-[2-(3-indolylethyl)]-N′-[2-(5-bromopyridyl)]thiourea (25) were the most active agents and inhibited the LTC4 release with low micromolar IC50 values of 4.9 and 6.1 μM, respectively. The hydroxylphenyl substituted compounds N-[2-(4-hydroxyphenyl)ethyl]-N′-[2-(5-chloropyridyl)]thiourea (37; IC50=12.6 μM), N-[2-(4-hydroxyphenyl)ethyl]-N′-[2-(5-bromopyridyl)]thiourea (50; IC50=16.8 μM) and N-[2-(4-hydroxyphenyl)ethyl]-N′-[2-(pyridyl)]thiourea (35; IC50=8.5 μM) were the most active pyridyl thiourea agents. Notably, the introduction of electron withdrawing or donating groups had a marked impact on the biological activity of these thiourea derivatives and the Hammett sigma values of their substituents were identified as predictors of their potency. In contrast, experimentally determined partition coefficient values did not correlate with the biological activity of the thiourea compounds which demonstrates that their liphophilicity is not an important factor controlling their mast cell inhibitory effects. These results establish the substituted halopyridyl, indolyl and naphthyl thiourea compounds as a new chemical class of anti-allergic agents inhibiting IgE receptor/FcεRI-mediated mast cell LTC4 release. Further lead optimization efforts may provide the basis for new and effective treatment as well as prevention programs for allergic asthma in clinical settings.
Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs
Bell,Cantrell,Hogberg,Jaskunas,Johansson,Jordan,Kinnick,Lind,Morin Jr.,Noreen,Oberg,Palkowitz,Parrish,Pranc,Sahlberg,Ternansky,Vasileff,Vrang,West,et al.
, p. 4929 - 4936 (2007/10/03)
A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 μM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 μM. The 50% cytotoxic dose in cell culture is >380 μM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2- pyridyl)-thiourea (62; LY300046 · HCl) as a candidate for clinical evaluation. LY300046 · HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.
