40507-75-3Relevant academic research and scientific papers
New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1
Coleman, Nichole,Brown, Brandon M.,Oliván-Viguera, Aida,Singh, Vikrant,Olmstead, Marilyn M.,Valero, Marta Sofia,K?hler, Ralf,Wulff, Heike
, p. 342 - 357 (2014/11/08)
Small-conductance (KCa2) and intermediate-conductance (K Ca3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate K Ca2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho [2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV 1.5, and NaV 1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1-/- mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation. Copyright
Swift and efficient synthesis of 4-phenylquinazolines: Involvement of N-heterocyclic carbene in the key cyclization step
Debray, Julien,Leveque, Jean-Marc,Philouze, Christian,Draye, Micheline,Demeunynck, Martine
supporting information; experimental part, p. 2092 - 2095 (2010/06/16)
"Chemical Equation Presented" An original route to 2-alkyamino-4-phenylquinazolines in three steps from simple (hetero)aromatic amines is reported here. The key step involves the intramolecular cyclization of benzoyl arylguanidines performed in [OMIm]Cl ionic liquid. The basic (hetero)aromatic guanidines deprotonate the imidazolium-based ionic liquid, thus triggering the cascade process ultimately leading to the intramolecular cyclization. This reaction is the first example of a Friedel-Crafts-type reaction in which an N-heterocyclic carbene is involved in the formation of the electrophilic intermediate.
Synthesis of N-(2-imidazolin-2-yl)-N-(4-indanyl) amine (indanazoline)
May
, p. 1733 - 1737 (2007/10/02)
The synthesis of the new vasoconstrictive agent N-(2,3-Dihydro-1H-indan-4-yl)-2.5-dihydro-1H-imidazol-2-amine (indanazoline, Farial) and the proof of its structure by spectroscopic methods is reported.
