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Publication Abstract from PubMed

Squalene synthase is one of the most promising pharmaceutical targets to treat hyperlipidemia. Inhibition of the squalene synthase causes a decrease in the hepatic cholesterol concentration. We have already reported the design and synthesis of highly potent benzhydrol-type squalene inhibitors. Although these templates showed unique and potent cyclic active conformations via intramolecular hydrogen bonds, the in vivo cholesterol-lowering efficacy was insufficient. We attempted to improve their potential as an orally active medicine. In our medicinal chemistry effort, cyclized 11-membered ring templates were acquired. The novel series of compounds exhibited potent squalene synthase inhibitory activity, and one of the derivatives, isomer A-(1S, 3R)-14i, showed plasma lipid-lowering efficacy in hamster and marmoset repeated-dose studies. Our findings provide valuable insights into the design and development of novel and unique 11-membered ring-type highly potent squalene synthase inhibitors.

Discovery of Novel 11-Membered Templates as Squalene Synthase Inhibitors.,Haginoya N, Suzuki M, Suzuki M, Ishigai Y, Terayama K, Kanda A, Sugita K J Med Chem. 2024 Apr 11;67(7):5305-5314. doi: 10.1021/acs.jmedchem.3c01500. Epub , 2024 Mar 22. PMID:38517948^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.