| Literature DB >> 29878763 |
Allyn T Londregan1, Liuqing Wei1, Jun Xiao1, Nathanael G Lintner2, Donna Petersen3, Robert G Dullea4, Kim F McClure5, Michael W Bolt6, Joseph S Warmus1, Steven B Coffey1, Chris Limberakis1, Julien Genovino1, Benjamin A Thuma1, Kevin D Hesp1, Gary E Aspnes5, Benjamin Reidich4, Christopher T Salatto4, Jeffrey R Chabot7, Jamie H D Cate2,8,9,10, Spiros Liras5, David W Piotrowski1.
Abstract
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.Entities:
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Year: 2018 PMID： 29878763 DOI： 10.1021/acs.jmedchem.8b00650
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446