3-[(5-Chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl ]-1,3,4-oxadiazol-2(3H)-one, BMS-191011:  Opener of Large-Conductance Ca²⁺-Activated Potassium (Maxi-K) Channels, Identification, Solubility, and SAR

Abstract

Compound 8a (BMS-191011), an opener of the cloned large-conductance, Ca2+-activated potassium (maxi-K) channel, demonstrated efficacy in in vivo stroke models, which led to its nomination as a candidate for clinical evaluation. Its maxi-K channel opening properties were consistent with its structural topology, being derived by combining elements from other known maxi-K openers. However, 8a suffered from poor aqueous solubility, which complicated elucidation of SAR during in vitro evaluation. The activity of 8a in in vivo stroke models and studies directed toward improving its solubility are reported herein. Enhanced solubility was achieved by appending heterocycles to the 8a scaffold, and a notable observation was made that inclusion of a simple amino group (anilines 8k and 8l) yielded excellent in vitro maxi-K ion channel opening activity and enhanced brain-to-plasma partitioning compared to the appended heterocycles.

Rapid and mild silylation of β‐amino alcohols at room temperature mediated by N‐methylimidazole for enhanced detectability by gas chromatography/electron ionization mass spectrometry

“…5). Mass spectra for all PDMS-derivatized alcohols (20)(21)(22)(23)(24)(25)(26)(27)(28)(29) are provided in the Supporting Information.…”

BMS-191011, an Opener of Large-Conductance Ca2+-Activated Potassium Channels, Dilates Rat Retinal Arterioles in Vivo

“…In this study, we assessed the effects of BMS-191011, which is a newly developed BK Ca channel opener 16,17) and the prototype BK Ca channel opener NS 1619 18) on the rat retinal circulation. We found that both BMS-191011 and NS 1619 caused the vasodilator responses of retinal arterioles in vivo; however, the responses to BMS-191011, but not to NS 1619, were diminished by intravitreal injection of iberiotoxin.…”

“…[13][14][15] However, the role of BK Ca channels in regulation of the retinal circulation remains unclear. The purpose of the present study, therefore, was to examine effects of two BK Ca channel openers, BMS-191011 16,17) and NS 1619, 18) on the rat retinal arterioles in vivo.…”

Synthesis of functionally substituted of 5-aryl-1,2,4-triazol-3-ones.

“…1,2,4-Триазол-3-оны представляют интерес, главным образом, как фармакологически значи-мые соединения, активность которых зависит от характера заместителей у атомов N-2, N-4 и C-5 [1][2][3][4]. Среди них обнаружены вещества с противоопухолевыми свойствами [1], агонисты PPAR рецепторов [2] и антагонисты нейрокинина 1 (NK 1 ) [3].…”

“…Среди них обнаружены вещества с противоопухолевыми свойствами [1], агонисты PPAR рецепторов [2] и антагонисты нейрокинина 1 (NK 1 ) [3]. 2,5-Биарил-1,2,4-триазол-3-оны и 4,5-биарил-1,2,4-триазол-3-оны известны как активаторы калиевых (Maxi-K2) каналов [4]. Триазолоны могут найти применение и в аналитических целях -в качестве хемосенсоров ка-тионов Hg 2+ и Cu 2+ [5].…”