- Pyrazole-3/5-carboxylic acids from 3/5-trifluoromethyl NH-pyrazoles
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We report here the transformation of 3/5-trifluoromethylpyrazoles derivative into the corresponding NH-pyrazole-3/5-carboxylic acids. Moreover, from 4- or 5-iodinated-3/5-trifluoromethylpyrazoles building blocks and the use of Suzuki-Miyaura or Negishi reactions followed by the trifluoromethyl hydrolysis, we illustrate short and original accesses to many series of NH-pyrazole-3/5-carboxylic acids otherwise difficult to prepare.
- Ermolenko, Mikhail S.,Guillou, Sandrine,Janin, Yves L.
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p. 257 - 263
(2013/01/15)
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- Pyrazole derivatives as partial agonists for the nicotinic acid receptor
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Nicotinic acid as a hypolipidemic agent appears unique due to its potential to increase HDL cholesterol levels to a greater extent than other drugs. However, it has some side effects, among which severe skin flushing is the most frequent and often limits patients' compliance. In a search for novel agonists for the recently identified and cloned G protein-coupled nicotinic acid receptor, we synthesized a series of substituted pyrazole-3-carboxylic acids that proved to have substantial affinity for this receptor. The affinities were measured by inhibition of [3H] nicotinic acid binding to rat spleen membranes. Potencies and intrinsic activities relative to nicotinic acid were determined by their effects on [35S]GTPγS binding to rat adipocyte and spleen membranes. Interestingly, most compounds were partial agonists. In particular, 2-diazabicyclo-[3,3,O 4,8]octa-3,8-diene-3-carboxylic acid (4c) and 5-propylpyrazole-3-carboxylic acid (4f) proved active with Ki values of approximately 0.15 μM and EC50 values of approximately 6 μM, while their intrinsic activity was only ~50% when compared to nicotinic acid. Even slightly more active was 5-butylpyrazole-3-carboxylic acid (4g) with a Ki value of 0.072 μM, an EC50 value of 4.12 μM, and a relative intrinsic activity of 75%. Of the aralkyl derivatives, 4q (5-(3-chlorobenzyl)pyrazole-3-carboxylic acid) was the most active with a relatively low intrinsic activity of 39%. Partial agonism of the pyrazole derivatives was confirmed by inhibition of G protein activation in response to nicotinic acid by these compounds. The pyrazoles both inhibited the maximum effect elicited by 100 μM nicotinic acid and concentration dependently shifted nicotinic acid concentration-response curves to the right, pointing to a competive mechanism of action.
- Van Herk,Brussee,Van den Nieuwendijk,Van der Klein,IJzerman,Stannek,Burmeister,Lorenzen
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p. 3945 - 3951
(2007/10/03)
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- CLEAVAGE REACTIONS USING BASIC HYDROGEN PEROXIDE. A METHOD FOR DEBLOCKING p-NITROBENZYL PROTECTED BASES AND PHENOLS
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The hydrolysis of certain nitriles with basic hydrogen peroxide is accompanied by an oxidative cleavage reaction giving the lower homologue carboxylic acid.Under the same conditions, p-nitrobenzylated bases and phenols yield the corresponding N-H base or phenol respectively.
- Balasuriya, Rohan,Chandler, Simon J.,Cook, Michael J.,Hardstone, David J.
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p. 1385 - 1386
(2007/10/02)
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