- Neladenoson Bialanate Hydrochloride: A Prodrug of a Partial Adenosine A1 Receptor Agonist for the Chronic Treatment of Heart Diseases
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Adenosine is known to be released under a variety of physiological and pathophysiological conditions to facilitate the protection and regeneration of injured ischemic tissues. The activation of myocardial adenosine A1 receptors (A1Rs) has been shown to inhibit myocardial pathologies associated with ischemia and reperfusion injury, suggesting several options for new cardiovascular therapies. When full A1R agonists are used, the desired protective and regenerative cardiovascular effects are usually overshadowed by unintended pharmacological effects such as induction of bradycardia, atrioventricular (AV) blocks, and sedation. These unwanted effects can be overcome by using partial A1R agonists. Starting from previously reported capadenoson we evaluated options to tailor A1R agonists to a specific partiality range, thereby optimizing the therapeutic window. This led to the identification of the potent and selective agonist neladenoson, which shows the desired partial response on the A1R, resulting in cardioprotection without sedative effects or cardiac AV blocks. To circumvent solubility and formulation issues for neladenoson, a prodrug approach was pursued. The dipeptide ester neladenoson bialanate hydrochloride showed significantly improved solubility and exposure after oral administration. Neladenoson bialanate hydrochloride is currently being evaluated in clinical trials for the treatment of heart failure.
- Meibom, Daniel,Albrecht-Küpper, Barbara,Diedrichs, Nicole,Hübsch, Walter,Kast, Raimund,Kr?mer, Thomas,Krenz, Ursula,Lerchen, Hans-Georg,Mittendorf, Joachim,Nell, Peter G.,Süssmeier, Frank,Vakalopoulos, Alexandros,Zimmermann, Katja
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supporting information
p. 728 - 737
(2017/05/26)
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- SUBSTITUTED ARYLOXAZOLES AND THEIR USE
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The present application relates to novel substituted aryloxazole derivatives, a method for the production thereof, the use thereof for the treatment and/or prophylaxis of diseases and the use thereof for the production of drugs for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of cardiovascular and metabolic disorders.
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Page/Page column 26
(2011/06/23)
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- Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: Structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109
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Following the discovery of a new series of benzimidazole derivatives bearing a diarylmethyl group as inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase (HCV NS5B RdRp), we extended the structure-activity relationship (SAR) study to analogue
- Hirashima, Shintaro,Suzuki, Takayoshi,Ishida, Tomio,Noji, Satoru,Yata, Shinji,Ando, Izuru,Komatsu, Masakazu,Ikeda, Satoru,Hashimoto, Hiromasa
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p. 4721 - 4736
(2007/10/03)
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- N-H Insertion reactions of rhodium carbenoids. Part 5: A convenient route to 1,3-azoles
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Dirhodium(II) carboxylate catalysed reaction of diazocarbonyl compounds 2 in the presence of primary amides 1 results in the formation of α-acylaminoketones 3 (12 examples) by N-H insertion reaction of the intermediate rhodium carbene. The 1,4-dicarbonyl
- Davies, James R.,Kane, Peter D.,Moody, Christopher J.
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p. 3967 - 3977
(2007/10/03)
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