Novel 4,1-benzoxazepine derivatives with potent squalene synthase inhibitory activities

Miki, Takashi; Kori, Masakuni; Mabuchi, Hiroshi; Banno, Hiroshi; Tozawa, Ryu ichi; Nakamura, Masahira; Itokawa, Shigekazu; Sugiyama, Yasuo; Yukimasa, Hidefumi

doi:10.1016/s0968-0896(01)00290-5

Cited by 32 publications

(14 citation statements)

References 13 publications

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“…SAR optimization led to the discovery of analog 46a , with low nanomolar potency in inhibiting both rat and HepG2 SQS (Miki et al, 2002b). Pharmacokinetic investigations revealed that the primary metabolite of 46a is the CYP-450 product 46b , which is rapidly eliminated in the urine, but is also active in inhibiting SQS.…”

Section: Isoprenoids Fpps/ggpps and Neurodegeneration—the Current Hypmentioning

confidence: 99%

Human isoprenoid synthase enzymes as therapeutic targets

et al. 2014

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In the human body, the complex biochemical network known as the mevalonate pathway is responsible for the biosynthesis of all isoprenoids, which consists of a vast array of metabolites that are vital for proper cellular functions. Two key isoprenoids, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are responsible for the post-translational prenylation of small GTP-binding proteins, and serve as the biosynthetic precursors to numerous other biomolecules. The down-stream metabolite of FPP and GGPP is squalene, the precursor to steroids, bile acids, lipoproteins, and vitamin D. In the past, interest in prenyl synthase inhibitors focused mainly on the role of the FPP in lytic bone diseases. More recently pre-clinical and clinical studies have strongly implicated high levels of protein prenylation in a plethora of human diseases, including non-skeletal cancers, the progression of neurodegenerative diseases and cardiovascular diseases. In this review, we focus mainly on the potential therapeutic value of down-regulating the biosynthesis of FPP, GGPP, and squalene. We summarize the most recent drug discovery efforts and the structural data available that support the current on-going studies.

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Section: Isoprenoids Fpps/ggpps and Neurodegeneration—the Current Hypmentioning

confidence: 99%

Human isoprenoid synthase enzymes as therapeutic targets

et al. 2014

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“…Good oral bioavailability of 73 allowed its p.o. administration for in vivo evaluation in rat and marmoset where it effectively produced a reduction of plasma total cholesterol and non-HDL cholesterol by 32 and 64 %, respectively [108].…”

Section: Benzoxazepinesmentioning

confidence: 99%

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

Kourounakis

Katselou²,

Matralis³

et al. 2011

CMC

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Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better side-effect profile is expected for these inhibitors. Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8- dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships.

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“…Acylation of sterically or electronically deactivated anilines [33][34][35][36]. If Lewis acids such as ZnCl 2 are used as catalysts the formation of an acridine can compete with N-acylation (Bernthsen acridine synthesis; last reaction, Scheme 7.10).…”

Section: Sterically or Electronically Deactivated Aminesmentioning

confidence: 99%

The Acylation of Heteroatoms

Dörwald

2004

Side Reactions in Organic Synthesis

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Novel 4,1-benzoxazepine derivatives with potent squalene synthase inhibitory activities

Cited by 32 publications

References 13 publications

Human isoprenoid synthase enzymes as therapeutic targets

Human isoprenoid synthase enzymes as therapeutic targets

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

The Acylation of Heteroatoms

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