J-104,123, a novel and orally-active inhibitor of squalene synthase: Stereoselective synthesis and cholesterol lowering effects in dogs

Iwasawa, Yoshikazu; Shibata, Jun; Mitsuya, Morihiro; Hashimoto, Masaki; Hayashi, Masahiro; Kanno, Toshio; Sawasaki, Yoshio; Hisaka, Akihiro; Kamei, Takeshi; Tomimoto, Koji

doi:10.1016/0960-894x(96)00033-9

Cited by 16 publications

(15 citation statements)

References 6 publications

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“…One can speculate that the two aryl substituents, which are crucial for the high potency of this acid, bind to the sites intended for the farnesyl chains of the two molecules of substrate. However, J-104118 showed poor oral absorption in dogs whereas its monocarboxylic acid active analogue, together with the monocarboxylic acid analogue J-104123 (40) (containing a naphthyl group instead of the biphenyl moiety) provided a significant cholesterol lowering effect after oral dosing in dogs [90].…”

Section: Dicarboxylic Acid Derivativesmentioning

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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Section: Dicarboxylic Acid Derivativesmentioning

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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“…J-104,118 is a highly potent dicarboxylic acid (IC 50 = 0.52 nM) that is more efficacious than zaragozic acid A following oral administration to mice [19]. The monocarboxylate J-104,123 maintains significant in vitro activity (IC 50 = 2.5 nM), provides approximately 50-fold greater plasma drug exposure following oral administration to dogs, and was the first squalene synthase inhibitor to lower plasma cholesterol in this species [20]. Compound 17 (IC 50 = 0.84 nM) is a related inhibitor also prepared by Banyu [116].…”

Section: Other Carboxylic Acid-derived Compoundsmentioning

confidence: 99%

Squalene synthase inhibitors 1998

Rosenberg

1998

Expert Opinion on Therapeutic Patents

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Squalene synthase, the first enzyme in the cholesterol biosynthetic pathway dedicated to sterol synthesis, represents an attractive target for hypocholesterolaemic therapy. Whilst no squalene synthase inhibitors have yet reached clinical trials, the most advanced compounds in this class, exemplified by J-104,123 and RPR 107393, reduce plasma cholesterol following chronic oral dosing in animal models. This review summarises the recent patent and primary literature in this field.

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“…Optically active tricarboxylic acids (TCA) are widely found in biologically and pharmaceutically active compounds. Important natural compounds such as Fumonisin Bl [53][54][55][56][57][58][59][60][61][62][63] or pharmaceutical compounds such as J-104, 118 [64][65][66][67] contain tricarboxylic acid moiety and possess bioactivities ( Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

“…For instance, in the reported methods for the synthesis of tricarboxylic acid moiety of Fumonisins or J-104, 118, enantioselective syntheses were achieved by using chiral auxiliary 47,48,58,62) or optical resolution of racemic compound using stoichiometric amount of chiral amines. [64][65][66] In order to improve the efficiency of the synthesis of such compounds, we envisioned that Michael reaction of malonates to maleates and subsequent decarboxylation would afford the desired tricarboxylic acid derivatives.…”

Section: Introductionmentioning

confidence: 99%

Lithium Binaphtholate-Catalyzed Michael Reaction of Malonates with Maleates and Its Application to the Enantioselective Synthesis of Tricarboxylic Acid Derivatives

Sakamoto

Kaneko

Orito

et al. 2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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J-104,123, a novel and orally-active inhibitor of squalene synthase: Stereoselective synthesis and cholesterol lowering effects in dogs

Cited by 16 publications

References 6 publications

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

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

Squalene synthase inhibitors 1998

Lithium Binaphtholate-Catalyzed Michael Reaction of Malonates with Maleates and Its Application to the Enantioselective Synthesis of Tricarboxylic Acid Derivatives

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