126411-40-3Relevant academic research and scientific papers
Bisphosphonate esters interact with HMG-CoA reductase membrane domain to induce its degradation
Hashimoto, Yuichi,Ohgane, Kenji,Sagimori, Ikuya,Toyota, Yosuke,Yoshioka, Hiromasa
, (2020)
HMG-CoA reductase (HMGCR) is a rate-limiting enzyme in the cholesterol biosynthetic pathway, and its catalytic domain is the well-known target of cholesterol-lowering drugs, statins. HMGCR is subject to layers of negative feedback loops; excess cholesterol inhibits transcription of the gene, and lanosterols and oxysterols accelerate degradation of HMGCR. A class of synthetic small molecules, bisphosphonate esters exemplified by SR12813, has been known to induce accelerated degradation of HMGCR and reduce the serum cholesterol level. Although genetic and biochemical studies revealed that the accelerated degradation requires the membrane domain of HMGCR and Insig, an oxysterol sensor on the endoplasmic reticulum membrane, the direct target of the bisphosphonate esters remains unclear. In this study, we developed a potent photoaffinity probe of the bisphosphonate esters through preliminary structure–activity relationship study and demonstrated binding of the bisphosphonate esters to the HMGCR membrane domain. These results provide an important clue to understand the elusive mechanism of the SR12813-mediated HMGCR degradation and serve as a basis to develop more potent HMGCR degraders that target the non-catalytic, membrane domain of the enzyme.
Design, synthesis and P-gp induction activity of aryl phosphonate esters: Identification of tetraethyl-2-phenylethene-1,1-diyldiphosphonate as an orally bioavailable P-gp inducer
Manda, Sudhakar,Wani, Abubakar,Bharate, Sonali S.,Vishwakarma, Ram A.,Kumar, Ajay,Bharate, Sandip B.
supporting information, p. 1910 - 1915 (2016/10/22)
The clearance of amyloid-beta is mediated by the P-glycoprotein (P-gp) transporter pump located at the blood brain barrier. Therefore, the induction of P-gp has been considered as a potential therapeutic strategy for the treatment of Alzheimer's disease. The expression of P-gp is regulated through a nuclear receptor, pregnane X receptor (PXR). Thus, herein we investigated the potential of a known PXR activator, diphosphonate ester SR12813 (6a), for P-gp induction activity and further studied its structure-activity relationship. The diphosphonate ester SR12813 along with three series of analogs, viz. aryl alkylidene, aryl alkynyl, and aryl α-amino phosphonate esters, were synthesized and screened for P-gp induction activity in P-gp overexpressing adenocarcinoma LS180 cells using rhodamine 123 efflux assay. The parent compound SR12813 along with several new analogs displayed P-gp induction activity at 5 μM. Western blot analysis indicated that tetraethyl-2-phenylethene-1,1-diyldiphosphonate (6c) and tetraethyl-2-(anthracene-10-yl)ethene-1,1-diyldiphosphonate (6s) showed 7-8-fold increase in P-gp expression in LS180 cells. The diphosphonate ester 6c displayed excellent aqueous solubility, no cytochrome P450 inhibition liability and no efflux pump substrate liability. Furthermore, it exhibits an excellent oral pharmacokinetic profile in BALB/c mice with AUC0-∞ of 2067 ng h mL-1 and 37.6% oral bioavailability. The results presented here clearly indicate the potential of this scaffold to increase the clearance of brain Aβ across the BBB and thus its promise for development as a potential anti-Alzheimer agent.
