A Novel Class of Antihyperlipidemic Agents with Low Density Lipoprotein Receptor Up-Regulation via the Adaptor Protein Autosomal Recessive Hypercholesterolemia

Q1 · MEDICINE

Article

Author: Kino, Kouichi ; Asano, Shigehiro ; Ioriya, Katsuhisa ; Kitano, Masafumi ; Ueno, Yoshihide ; Uno, Shinsaku ; Tsuboya, Norie ; Ban, Hitoshi

We have previously reported compound 2 as a inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT) and up-regulator of the low density lipoprotein receptor (LDL-R) expression. In this study we focused on compound 2, a unique LDL-R up-regulator, and describe the discovery of a novel class of up-regulators of LDL-R. Replacement the methylene urea linker in compound 2 with an acylsulfonamide linker kept a potent LDL-R up-regulatory activity, and subsequent optimization work gave compound 39 as a highly potent LDL-R up-regulator (39; EC(25) = 0.047 microM). Compound 39 showed no ACAT inhibitory activity even at 1 microM. The sodium salts of compound 39 reduced plasma total and LDL cholesterol levels in a dose-dependent manner in an experimental animal model of hyperlipidemia. Moreover, we revealed in this study using RNA interference that autosomal recessive hypercholesterolemia (ARH), an adaptor protein of LDL-R, is essential for compound 39 up-regulation of LDL-R expression.

01 Jul 2009·Bioorganic & medicinal chemistryQ3 · MEDICINE

Synthesis and structure–activity relationships of N-(4-amino-2,6-diisopropylphenyl)-N’-(1,4-diarylpiperidine-4-yl)methylureas as anti-hyperlipidemic agents

Q3 · MEDICINE

Article

Author: Asano, Shigehiro ; Muraoka, Masami ; Kino, Koichi ; Ioriya, Katsuhisa ; Ban, Hitoshi

Based on 1,4-diarylpiperidine-4-methylureas, a new class of ACAT inhibitors, we examined in the study the SAR of a series of compounds prepared by replacing the substituent at the three aromatic parts. Introduction of long alkoxy group onto the phenyl moiety at the B-part was effective in improving both the inhibitory activity for ACAT and the up-regulatory activity for LDL-R expression. Particularly, 3-hydroxypropoxy group (43) on the phenyl moiety of B-part led to improved solubility, while keeping both biological activities. Compound 43 inhibited ACAT activity with an IC(50) value of 18 nM, which is superior to that of a known ACAT inhibitor, CI-1011. In addition, compound 43 revealed an LDL-R up-regulatory activity comparable to that of SMP-797. We therefore expect this compound to be a novel ACAT inhibitor.

01 Feb 2009·Bioorganic & medicinal chemistry lettersQ4 · MEDICINE

Novel 1,4-diarylpiperidine-4-methylureas as anti-hyperlipidemic agents: Dual effectors on acyl-CoA:cholesterol O-acyltransferase and low-density lipoprotein receptor expression

Q4 · MEDICINE

Article

Author: Asano, Shigehiro ; Kino, Kouichi ; Muraoka, Masami ; Ioriya, Katsuhisa ; Ban, Hitoshi

A family of 1,4-diarylpiperidine-4-methylureas were designed and synthesized as novel dual effectors on ACAT and LDL receptor expression. We examined SAR of the synthesized compounds focusing on substitution at the three aromatic parts of the starting compound 1 and succeeded in identifying essential substituents for inhibition of ACAT and up-regulation of hepatic LDL receptor expression. Especially, we found that compound 12f, which can easily be prepared, has biological properties comparable to those of SMP-797, a promising ACAT inhibitor. In addition, the in vitro effects of 12f on lipid metabolism were substantially superior to those of a known ACAT inhibitor, Avasimibe.

100 Deals associated with SMP-797

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Indication	Highest Phase	Country/Location	Organization	Date
Hypercholesterolemia	Phase 2	Europe	-	-
Hypercholesterolemia	Phase 2	-	Sumitomo Pharma Co., Ltd.	-

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