Quality by design (QbD) of amide isosteres: 5,5-Disubstituted isoxazolines as potent CRTh2 antagonists with favorable pharmacokinetic and drug-like properties |
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| Affiliation: | 1. Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. Discovery Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA;3. In vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;4. Immunology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;5. Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;1. School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi 324-8501, Japan;2. Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan;3. School of Pharmacy, Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa 245-0066, Japan;1. College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 34134, Republic of Korea;2. College of Pharmacy, Chungbuk National University, Cheongju 19421, Republic of Korea;1. College of Chemistry and Chemical Engineering, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China;2. College of Chemistry and Chemical Engineering, Sichuan University of Arts and Science, Dazhou 635000, PR China;3. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China;1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China;2. Department of Chemistry and Chemical Engineering, Jining University, Qufu 273155, PR China;3. Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, PR China;4. General Hospital, Tianjin Medical University, Tianjin 300052, PR China |
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| Abstract: | ![]()
Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties. |
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| Keywords: | Agonism/antagonism switch Quality by design (QbD) Amide isostere Isoxazolines Drug-like properties |
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