Core modification of substituted piperidines as Novel inhibitors of HDM2–p53 protein–protein interaction |
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| Institution: | 1. Merck Research Laboratories, Early Development and Discovery Sciences, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States;2. Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States;1. Laboratory of Organic Chemistry for Drug Development, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Sapporo 060-0812, Japan;2. Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Sapporo 060-0812, Japan;3. Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Sapporo 060-0812, Japan;4. Graduate School of Pharmaceutical Sciences, University of Shizuoka, Yada, Shizuoka 422-8526, Japan;1. Departamento de Química Orgánica, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC–Universidad de Zaragoza, 50009 Zaragoza, Spain;2. Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain;1. School of Chemistry and Chemical Engineering, University of Jinan, 336 West Road of Nan Xinzhuang, Jinan 250022, China;2. School of Biological Science and Technology, University of Jinan, 336 West Road of Nan Xinzhuang, Jinan 250022, China;1. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China;2. Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou 450001, China;3. Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK;4. College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA;5. Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China;6. Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou 450001, China;7. College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China;8. Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou 510033, China;9. College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China;1. Department of Bioinformatics, Applied Botany Centre (ABC), University School of Sciences, Gujarat University, Ahmedabad, 380009, India;2. Department of Botany, University School of Sciences, Gujarat University, Ahmedabad, 380009, India |
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| Abstract: | The discovery of 3,3-disubstituted piperidine 1 as novel p53–HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency. |
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| Keywords: | HDM2 p53 Protein–protein interaction Cancer |
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