119454-89-6Relevant articles and documents
Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory t cells in autoimmune diseases
Schmitz, Alexander,Sankaranarayanan, Ananthakrishnan,Azam, Philippe,Schmidt-Lassen, Kristina,Homerick, Daniel,Haensel, Wolfram,Wulff, Heike
, p. 1254 - 1270 (2005)
The lymphocyte K+ channel Kv1.3 constitutes an attractive pharmacological target for the selective suppression of terminally differentiated effector memory T (TEM) cells in T cell mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes. Unfortunately, none of the existing small molecule Kv1.3 blockers is selective, and many of them, such as correolide, 4-phenyl-4-[3-(methoxyphenyl)-3-oxo-2- azapropyl] cyclohexanone, and our own compound Psora-4 inhibit the cardiac K+ channel Kv1.5. By further exploring the structure activity relationship around Psora-4 through a combination of traditional medicinal chemistry and whole-cell patch-clamp, we identified a series of new phenoxyalkoxypsoralens that exhibit 2- to 50-fold selectivity for Kv1.3 over Kv1.5, depending on their exact substitution pattern. The most potent and "druglike" compound of this series, 5-(4-phenoxybutoxy)psoralen (PAP-1), blocks Kv1.3 in a use-dependent manner, with a Hill coefficient of 2 and an EC50 of 2 nM, by preferentially binding to the C-type inactivated state of the channel. PAP-1 is 23-fold selective over Kv1.5, 33- to 125-fold selective over other Kv1-family channels, and 500- to 7500-fold selective over Kv2.1, Kv3.1, Kv3.2, Kv4.2, HERG, calcium-activated K+ channels, Na+, Ca2+, and Cl- channels. PAP-1 does not exhibit cytotoxic or phototoxic effects, is negative in the Ames test, and affects cytochrome P450-dependent enzymes only at micromolar concentrations. PAP-1 potently inhibits the proliferation of human TEM cells and suppresses delayed type hypersensitivity, a TEM cell-mediated reaction, in rats. PAP-1 and several of its derivatives therefore constitute excellent new tools to further explore Kv1.3 as a target for immunosuppression and could potentially be developed into orally available immunomodulators. Copyright
Oxime Ethers: New Potent Insect Growth Regulators
Ohsumi, Tadashi,Hatakoshi, Makoto,Kisida, Hirosi,Matsuo, Noritada,Nakayama, Isamu,Itaya, Nobushige
, p. 3197 - 3202 (2007/10/02)
Oxime ethers containing a 4-phenoxyphenoxy group in the molecules were synthesized and their insect growth regulating (IGR) activities were studied.Of these new IGR's, propionaldehyde oxime O-2-(4-phenoxyphenoxy)ethyl ether and propionaldehyde oxime O-2-(phenoxyphenoxy)propyl ether were found to be most effective, having much higher activities than methoprene against larvae of Culex pipiens pallens and Musca domestica by the immersion method and medium method, respectively.In addition, the effects of steric isomerism of these compounds were examined; their IGR activities were found to have a close relationship to the juvenile hormone activity by the Galleria wax test.
