Identification of 4H,6H-[2]benzoxepino[4,5-c][1,2]oxazoles as novel squalene synthase inhibitors

Griebenow, Nils; Buchmueller, Anja; Kolkhof, Peter; Schamberger, Jens; Bischoff, Hilmar

doi:10.1016/j.bmcl.2011.04.092

Cited by 10 publications

(5 citation statements)

References 21 publications

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“…Because of its strategic location in this pathway, it is an attractive target for inhibition and for the development of novel, improved antihypercholesterolemic agents that may leave other nonsterol products of mevalonate metabolism unaffected. , Although the first SQS inhibitor that reached phase III clinical trials (TAK-475) was discontinued because of safety concerns at high doses, it is unclear if the toxicity of TAK-475 is a structure/metabolite- or mechanism-related effect. Furthermore, several studies on the discovery of novel SQS inhibitors have been published during the last couple of years, pointing out the intense research interest that exists in this scientific field. − …”

Section: Introductionmentioning

confidence: 99%

Design of Novel Potent Antihyperlipidemic Agents with Antioxidant/Anti-inflammatory Properties: Exploiting Phenothiazine’s Strong Antioxidant Activity

Matralis

Kourounakis

2014

J. Med. Chem.

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Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

Design of Novel Potent Antihyperlipidemic Agents with Antioxidant/Anti-inflammatory Properties: Exploiting Phenothiazine’s Strong Antioxidant Activity

Matralis

Kourounakis

2014

J. Med. Chem.

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“…Squalene synthase is an attractive target mainly because it is the first enzyme involved in the sterol biosynthesis. , The inhibitors of the enzyme do not inhibit nonsteroidal biomolecules. − Although there are already known inhibitors of squalene synthase, it is still difficult to confirm that these compounds have the required sufficient cholesterol lowering potential. ,,− …”

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confidence: 99%

Discovery of DF-461, a Potent Squalene Synthase Inhibitor

Ichikawa

Ohtsuka

Ohki

et al. 2013

ACS Med. Chem. Lett.

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ABSTRACT:We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure−activity studies and pharmacokinetics optimization on this series led to the identification of compound 23 (DF-461), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies.KEYWORDS: Squalene synthase, inhibitor, dyslipidemia, triazolobenzoxazepine I n recent years, the number of arteriosclerosis, ischemic heart diseases, and ischemic brain diseases attributed to arteriosclerosis is increasing around the world due to the spread of the Western dietary pattern and the growing number of elderly affected people. Hypercholesterolemia is one of the primary risk factors of arteriosclerosis. To treat the disease, it is effective to administer medicines for reducing the serum low density lipoprotein (LDL) cholesterol level. The cardiovascular risk reduction of hydroxymethylglutraryl-CoA (HMG-CoA) reductase inhibitors (statins) is principally attributed to their LDL lowering effects as demonstrated in numerous randomized clinical trials. 1−3 However, statins have potential adverse effects, such as myotoxicity, muscle pain, and, in very rare cases, rhabdomyolysis 4,5 because the inhibition of HMG-CoA reductase also interferes with the synthesis of many nonsteroidal isoprenoid molecules. Cerivastatin, one of the second generation statins, was withdrawn from the world market in 2001, due to its adverse effects. 6 Thus, it is preferable to prevent the cholesterol biosynthesis by targeting an enzyme, which lies downstream of farnesyl pyrophosphate in the cholesterol biosynthesis pathway, without interruption to the biosynthesis of essential physiological components, such as ubiquinone and dolichol.Squalene synthase is an attractive target mainly because it is the first enzyme involved in the sterol biosynthesis. 7,8 The inhibitors of the enzyme do not inhibit nonsteroidal biomolecules. 9−12 Although there are already known inhibitors of squalene synthase, it is still difficult to confirm that these compounds have the required sufficient cholesterol lowering potential. 7,8,13−18 Our research group has already reported the lead identifications and initial optimizations of two series of small molecule squalene synthase inhibitors; one is an open form benzhydrol series, another is a tricyclic pyrrolobenzoxazepine series, demonstrating plasma lipid-lowering efficacies in preclinical animal models.Exploratory medicinal chemistry efforts focused on initial lead 1. 19 The highly potent alkoxy-aminobenzhydrol compound 2 was obtained, 20 through incorporations of both the nipecotic acid part at the end of the side chain and the bulky alkoxy part at the aniline ring's ortho position; the benzhydrol compounds formed unique 11-membered ring active conformations with intramolecular hydrogen bonds, between the benzhydrol hydroxyl part and the side...

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“…A set of 34 compounds tested with the same assay has been collected from different references . The compounds cover diverse structures and the molecular bioactivities in IC 50 ranging from 0.59 to 3300 nM.…”

Section: Methodsmentioning

confidence: 99%

Identification of hit compounds for squalene synthase: Three‐dimensional quantitative structure‐activity relationship pharmacophore modeling, virtual screening, molecular docking, binding free energy calculation, and molecular dynamic simulation

Hou

Yan

Ma³

et al. 2017

Journal of Chemometrics

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Squalene synthase (SQS) is the key precursor in the synthesis of cholesterol. Located downstream in relation to hydroxy methylglutaryl coenzyme A reductase and having no influence on the formation of biologically necessary isoprenoids make it an interesting target for the development of cholesterol lowering drugs with fewer side effects. To discover novel SQS inhibitors, three-dimensional quantitative structure-activity relationship pharmacophore models were built and further validated by cost function analysis, test set validation, and decoy set validation to obtain a reliable model for virtual screening against a database that contains 5.5 million compounds. The interactions between SQS and the ligands were predicted by an integrated protocol that contains molecular docking, molecular mechanics/generalized born surface area, and molecular dynamic simulation. After that, five compounds with best binding affinities and binding modes were obtained as potential hits for further study and three of them showed inhibitory effects against SQS.KEYWORDS binding free energy, molecular dynamic simulation, pharmacophore model, SQSIs, virtual screening Manzhou Hou and Guoyi Yan contributed equally to this work.

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Identification of 4H,6H-[2]benzoxepino[4,5-c][1,2]oxazoles as novel squalene synthase inhibitors

Cited by 10 publications

References 21 publications

Design of Novel Potent Antihyperlipidemic Agents with Antioxidant/Anti-inflammatory Properties: Exploiting Phenothiazine’s Strong Antioxidant Activity

Design of Novel Potent Antihyperlipidemic Agents with Antioxidant/Anti-inflammatory Properties: Exploiting Phenothiazine’s Strong Antioxidant Activity

Discovery of DF-461, a Potent Squalene Synthase Inhibitor

Identification of hit compounds for squalene synthase: Three‐dimensional quantitative structure‐activity relationship pharmacophore modeling, virtual screening, molecular docking, binding free energy calculation, and molecular dynamic simulation

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