Discovery of novel,potent, and orally bioavailable pyrido[2,3-d][1]benzazepin-6-one antagonists for parathyroid hormone receptor 1 |
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| Institution: | 1. Facultad de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, 04510 Coyoacán, Mexico, DF, Mexico;2. Instituto de Investigaciones Quıímico-Biológicas, Ciudad Universitaria, Universidad de San Nicolás de Hidalgo Edificio B-2, Morelia, Mich. 58030, Mexico;1. Dipartimento di NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy;2. Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA;3. Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK;4. Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk 634050, Russia;5. Department of Chemistry, Altai State Technical University, Barnaul, Russia;6. Institute of Chinese Medical Sciences, University of Macau, Macau;1. School of Chemistry & Chemical Engineering, Tianjin University of Technology, Tianjin, 300384, PR China;2. Key Laboratory of Chemical Synthesis and Pollution Control of Sichuan Province, School of Chemistry and Chemical Engineering, China West Normal University, Nanchong, 637002, PR China;1. Faculty of Chemistry, Department of Organic Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland;2. PPSM, ENS Cachan, CNRS, UniverSud, 61 Avenue President Wilson, 94230 Cachan, France;3. Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089 Warszawa, Poland |
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| Abstract: | Structural modification of a 1,4-benzodiazepin-2-one-based PTHR1 antagonist 5, a novel type of PTHR1 antagonist previously synthesized in our laboratories, yielded compound 10, which had better chemical stability than compound 5. Successive optimization of the lead 10 improved aqueous solubility, metabolic stability, and animal pharmacokinetics, culminating in the identification of DS37571084 (12). Our study paves the way for the discovery of novel and orally bioavailable PTHR1 antagonists. |
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| Keywords: | Parathyroid hormone (PTH) PTH type 1 receptor (PTHR1) antagonist Dibenzazepinone Pyrido[2 3-d][1]benzazepin-6-one Scaffold hopping |
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