Abstract
The dissolution of the antihypertensive AT1 antagonist olmesartan in methanol generates in situ a new highly bioactive methyl ether analogue via SN1 mechanism involving an intramolecular proton transfer from carboxyl to hydroxyl group. Theoretical calculations confirmed the thermodynamic control preference of methyl ether versus the antagonistic product methyl ester. Α facile synthetic method for olmesartan methyl ether from olmesartan or olmesartan medoxomil is also described. Interestingly, the introduction of the methyl group to olmesartan did not alter its pharmacological properties. This observation opens new avenues in the synthesis of novel drugs, since hydroxyl and carboxylate groups have an orthogonal relationship in many drugs.
Keywords: Angiotensin II AT1 receptor blocker, drug discovery, ethers, NMR, olmesartan, synthetic method, theoretical calculations.
Combinatorial Chemistry & High Throughput Screening
Title:An Efficient Synthetic Method and Theoretical Calculations of Olmesartan Methyl Ether: Study of Biological Function of AT1 Antagonism
Volume: 17 Issue: 8
Author(s): Dimitrios Ntountaniotis, George Agelis, Amalia Resvani, Maria Halabalaki, George Liapakis, Katerina Spyridaki, Simona Golic Grdadolnik, Franci Merzel, Sarantos Kostidis, Constantinos Potamitis, Theodore Tselios, John Matsoukas, Leandros Alexios Skaltsounis and Thomas Mavromoustakos
Affiliation:
Keywords: Angiotensin II AT1 receptor blocker, drug discovery, ethers, NMR, olmesartan, synthetic method, theoretical calculations.
Abstract: The dissolution of the antihypertensive AT1 antagonist olmesartan in methanol generates in situ a new highly bioactive methyl ether analogue via SN1 mechanism involving an intramolecular proton transfer from carboxyl to hydroxyl group. Theoretical calculations confirmed the thermodynamic control preference of methyl ether versus the antagonistic product methyl ester. Α facile synthetic method for olmesartan methyl ether from olmesartan or olmesartan medoxomil is also described. Interestingly, the introduction of the methyl group to olmesartan did not alter its pharmacological properties. This observation opens new avenues in the synthesis of novel drugs, since hydroxyl and carboxylate groups have an orthogonal relationship in many drugs.
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Ntountaniotis Dimitrios, Agelis George, Resvani Amalia, Halabalaki Maria, Liapakis George, Spyridaki Katerina, Grdadolnik Golic Simona, Merzel Franci, Kostidis Sarantos, Potamitis Constantinos, Tselios Theodore, Matsoukas John, Skaltsounis Alexios Leandros and Mavromoustakos Thomas, An Efficient Synthetic Method and Theoretical Calculations of Olmesartan Methyl Ether: Study of Biological Function of AT1 Antagonism, Combinatorial Chemistry & High Throughput Screening 2014; 17 (8) . https://dx.doi.org/10.2174/138620731708140922171503
DOI https://dx.doi.org/10.2174/138620731708140922171503 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
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