Discovery of acylurea isosteres of 2-acylaminothiadiazole in the azaxanthene series of glucocorticoid receptor agonists |
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| Affiliation: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;2. Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;3. Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;4. Department of In Vitro Sciences, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;1. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;2. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;3. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Support Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;1. Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland;2. Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan |
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| Abstract: | Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described. |
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| Keywords: | Acylurea Imide Isostere Glucocorticoid receptor Non-steroidal glucocorticoid receptor agonists |
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