Identification of a novel hormone sensitive lipase inhibitor with a reduced potential of reactive metabolites formation

Ogiyama, Tomoko; Yamaguchi, Mitsuhiro; Kurikawa, Nobuya; Honzumi, Shoko; Yamamoto, Yuka; Sugiyama, Daisuke; Takakusa, Hideo; Inoue, Shinichi

doi:10.1016/j.bmc.2017.02.045

Cited by 13 publications

(8 citation statements)

References 23 publications

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“…HSL is also localized in adipose tissues and hydrolyzes not only cholesteryl esters but also glycerolipids, such as triacylglycerols and diacylglycerols, which are mainly composed of monounsaturated fatty acids, indicating a broad substrate specificity 31 , 32 . Consistently, treatment of MA-10 cells with HSL-IN-1, a selective and potent inhibitor of HSL 26 , reduced the basal levels of various FFA species including oleic acid (18:1n-9) (Supplementary Fig. 13 ).…”

Section: Discussionsupporting

confidence: 52%

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Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production

Lee-Okada

Yokomizo

2022

Commun Biol

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Highly unsaturated fatty acids (HUFAs) are fatty acids with more than three double bonds in the molecule. Mammalian testes contain very high levels of omega-6 HUFAs compared with other tissues. However, the metabolic and biological significance of these HUFAs in the mammalian testis is poorly understood. Here we show that Leydig cells vigorously synthesize omega-6 HUFAs to facilitate male sex hormone production. In the testis, FADS2 (Fatty acid desaturase 2), the rate-limiting enzyme for HUFA biosynthesis, is highly expressed in Leydig cells. In this study, pharmacological and genetic inhibition of FADS2 drastically reduces the production of omega-6 HUFAs and male steroid hormones in Leydig cells; this reduction is significantly rescued by supplementation with omega-6 HUFAs. Mechanistically, hormone-sensitive lipase (HSL; also called LIPE), a lipase that supplies free cholesterol for steroid hormone production, preferentially hydrolyzes HUFA-containing cholesteryl esters as substrates. Taken together, our results demonstrate that Leydig cells highly express FADS2 to facilitate male steroid hormone production by accumulating omega-6 HUFA-containing cholesteryl esters, which serve as preferred substrates for HSL. These findings unveil a previously unrecognized importance of omega-6 HUFAs in the mammalian male reproductive system.

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Section: Discussionsupporting

confidence: 52%

“…13 ). We also utilized HSL-IN-1, a selective and potent inhibitor of HSL 26 , to detect HSL-dependent FFA liberation. When the cells were stimulated with hCG, the levels of ARA and DPAn-6 were markedly increased (Fig.…”

Section: Resultsmentioning

confidence: 99%

Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production

Lee-Okada

Yokomizo

2022

Commun Biol

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“…Nevertheless, the compound suffered from bioactivation liability (Ogiyama et al, 2016). Recently, the latter inhibitor has been synthetically modified to significantly reduced bioactivation potential (Ogiyama et al, 2017). Lipase inhibitors from natural resources have also been reported.…”

Section: Discussionmentioning

confidence: 99%

The herbicide quinclorac as potent lipase inhibitor: Discovery via virtual screening and in vitro/in vivo validation

2019

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Lipolysis is primarily controlled by the stepwise action of hormone‐sensitive lipase (HSL) and monoglyceride lipase (MGL) to release free fatty acids and glycerol. A high level of circulating free fatty acids is well‐known to mediate insulin resistance. Thus, the need to discover lipase inhibitors against both enzyme systems remains urgent. Agrochemicals are tightly regulated chemicals and therefore are potential source of new medicinal agents. Accordingly, we implemented a computational workflow to search for new lipase inhibitory leads by virtually screening commercial agrochemicals against HSL and MGL employing binding pharmacophores and docking experiments. Ten agrochemicals were identified as potential lipase inhibitors, out of which quinclorac, a safe herbicide, achieved high‐ranking score. Subsequent in vitro evaluation against rat epididymal lipase activity showed quinclorac to exhibit nanomolar anti‐lipase IC50. Subsequent in vivo testing showed quinclorac to significantly decrease blood glycerol levels after acute exposure (150 mg/kg) and multiple dosing (50 or 25 mg/kg) (p < 0.05).

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“…GSH-Trapping Assay. 31 For the GSH-trapping experiments, each test compound (500 μM) was incubated with HLM (2 mg of protein/ mL) supplemented with an NADPH-generating system and an equimolar mixture of GSH and stable isotope-labeled GSH ([ 13 C 2 , 15 N-Gly]GSH). After 60 min incubation, the reaction was terminated with MeCN containing n-PrOH, followed by centrifugation and concentration of the supernatant.…”

Section: -(1-methyl-1h-pyrazol-5-yl)ethan-1-ol (4a)mentioning

confidence: 99%

Discovery of DS-1971a, a Potent, Selective Na_V1.7 Inhibitor

et al. 2020

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A highly potent, selective NaV1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.

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Identification of a novel hormone sensitive lipase inhibitor with a reduced potential of reactive metabolites formation

Cited by 13 publications

References 23 publications

Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production

Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production

The herbicide quinclorac as potent lipase inhibitor: Discovery via virtual screening and in vitro/in vivo validation

Discovery of DS-1971a, a Potent, Selective Na_V1.7 Inhibitor

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Identification of a novel hormone sensitive lipase inhibitor with a reduced potential of reactive metabolites formation

Cited by 13 publications

References 23 publications

Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production

Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production

The herbicide quinclorac as potent lipase inhibitor: Discovery via virtual screening and in vitro/in vivo validation

Discovery of DS-1971a, a Potent, Selective NaV1.7 Inhibitor

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Discovery of DS-1971a, a Potent, Selective Na_V1.7 Inhibitor