Shigehiro Asano

5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidines as novel class of potent and highly selective CaMKII inhibitors.

A novel series of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines containing substituted phenyl sulfonamide are synthesized and evaluated for their inhibitory activity against CaMKII. Substituents on the phenyl group had significant impact on CaMKII inhibition, in particular, the inhibitory activity of 8p was 25-fold higher than that of KN-93, a known CaMKII inhibitor. Michaelis-Menten analysis of a representative compound suggested that the synthesized pyrimidines are calmodulin non-competitive inhibitors. Finally, 8p exhibited more than 100-fold higher selectivity for CaMKII over five types of off-target kinases.

Synthesis and structure based optimization of 2-(4-phenoxybenzoyl)-5-hydroxyindole as a novel CaMKII inhibitor.

Based on 2-(4-phenoxybenzoyl)-5-hydroxyindole (2), a novel structural class of CaMKII inhibitors were synthesized and further optimized. The strong acidity of the hydroxyl group and the lipophilic group at the 4 and 6-positions were found to be necessary for strong CaMKII inhibition. Compound 25 was identified as a promising compound with 50-fold more potent inhibitory activity for CaMKII than 2. Compound 25 also showed high selectivity for CaMKII over off-target kinases.

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

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.

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

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.

Structure and activity relationship of 2-(substituted benzoyl)-hydroxyindoles as novel CaMKII inhibitors

A series of novel 2-substituted-5-hydroxyindoles were synthesized and evaluated for their inhibitory activity against CaMKII. Structure and activity relationship results indicated that potent inhibitory activity could be achieved by modification at the para-position of the phenyl ring of the high throughput screening hit compound 2. Among the prepared compounds, we identified 14 as a novel CaMKII inhibitor with an activity stronger than that of KN-93, a known CaMKII inhibitor.

A convenient one-pot preparation of n-substituted 4-phenylpiperidines

N-Substituted 4-phenylpiperidines were readily synthesized by one-pot cyclization of diols with amines via bis-triflate intermediates. The new synthesis under mild conditions gave various N-substituted 4-phenylpiperidines in moderate to good yields.

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

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.