- Development of a scaleable synthesis of a partial nicotinic acid receptor agonist
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A practical and efficient synthesis of 1,4,5,6-tetrahydro-3-(1Htetrazol- 5-yl)cyclopenta[c]pyrazole, 1, is described. A new one-pot process has been developed, starting from the commercially available 1H-tetrazole-5-carboxylic acid-ethyl ester sodium salt which is reacted in a pseudo-Claisen condensation reaction with cyclopentanone, followed by the addition of hydrazine.
- Wilson, Robert D.,Cleator, Ed,Ashwood, Michael S.,Bio, Matthew M.,Brands, Karel M.J.,Davies, Antony J.,Dolling, Ulf-H,Emerson, Khateeta M.,Gibb, Andrew D.,Hands, David,McKeown, Arlene E.,Oliver, Steven F.,Reamer, Robert A.,Sheen, Faye J.,Stewart, Gavin W.,Zhou, George X.
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experimental part
p. 543 - 547
(2010/04/22)
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- 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): A partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice
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The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro- cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism,
- Semple, Graeme,Skinner, Philip J.,Gharbaoui, Tawfik,Shin, Young-Jun,Jung, Jae-Kyu,Cherrier, Martin C.,Webb, Peter J.,Tamura, Susan Y.,Boatman, P. Douglas,Sage, Carleton R.,Schrader, Thomas O.,Chen, Ruoping,Colletti, Steven L.,Tata, James R.,Waters, M. Gerard,Cheng, Kang,Taggart, Andrew K.,Cai, Tian-Quan,Carballo-Jane, Ester,Behan, Dominic P.,Connolly, Daniel T.,Richman, Jeremy G.
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experimental part
p. 5101 - 5108
(2009/08/07)
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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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