Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents
| Autor: | Liuqing Wei, Jun Xiao, Joseph S. Warmus, Jeffrey R. Chabot, Robert Dullea, Christopher T. Salatto, David W. Piotrowski, Benjamin A. Thuma, Donna N. Petersen, Chris Limberakis, Julien Genovino, Steven B. Coffey, Michael W. Bolt, Kim F. McClure, Kevin D. Hesp, Spiros Liras, Jamie H. D. Cate, Nathanael G. Lintner, Allyn T. Londregan, Gary Erik Aspnes, Benjamin Reidich |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine 01 natural sciences Rats Sprague-Dawley Structure-Activity Relationship 03 medical and health sciences In vivo Drug Discovery Animals Structure–activity relationship Protease Inhibitors 010405 organic chemistry Chemistry PCSK9 PCSK9 Inhibitors Subtilisin Hit to lead Proprotein convertase Small molecule Rats 0104 chemical sciences 030104 developmental biology Biochemistry Drug Design Molecular Medicine Kexin Safety |
| Zdroj: | Journal of Medicinal Chemistry. 61:5704-5718 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, 7l demonstrated an improved safety profile vs lead 7f. We hypothesize that the improved safety profile is related to diminished binding of 7l to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of 7l stalling of off-target proteins. |
| Databáze: | OpenAIRE |
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