Derivatives of the natural product 11-hydroxy-3-[(S)-1-hydroxy-3-methylbutyl]-4-methoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]dioxocin-5-one 1 were studied as novel CETP inhibitors. Compound 2 was identified from HTS as a micromolar inhibitor. The compound suffered from very low stability in plasma. Optimisation by partial synthesis started from 1 and led to low-nanomolar inhibitors with good stability in rat plasma.
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Advances in the pharmacological management of hyperlipidemia through the use of combination therapies.
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December 2024
Department of Metabolic Medicine/Chemical Pathology Guy's, St Thomas' Hospitals, London, UK.
Introduction: Lipid-lowering therapies are well established for the treatment of cardiovascular disease (CVD). Historically monotherapy studies have been performed, but the introduction of statins has led to these drugs being recognized as baseline therapies and to the investigation of combination therapy of both older and newer medications with them.
Areas Covered: Surrogate marker studies have shown additive effects on LDL-C, triglycerides and HDL-C of combination therapies with statins and these have extended to lipoprotein (a).
Optimizing treatment of cardiovascular risk factors in cerebral small vessel disease using genetics.
Brain
December 2024
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK.
Article Synopsis
- Cerebral small vessel disease (cSVD) is linked to serious conditions like lacunar stroke and vascular dementia, but there's limited research on how managing traditional cardiovascular risk factors can specifically reduce stroke risk in cSVD.
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Novel Insights into Causal Effects of Lipid and Lipid-Lowering Targets with Autoimmune Thyroid Disease: A Mendelian Randomization Study.
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Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, People's Republic of China.
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View Article and Find Full Text PDFCholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity.
Curr Opin Lipidol
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NewAmsterdam Pharma B.V., Naarden, The Netherlands.
Purpose Of Review: To review the evidence and describe the biological plausibility for the benefits of inhibiting cholesteryl ester transfer protein (CETP) on multiple organ systems through modification of lipoprotein metabolism.
Recent Findings: Results from observational studies, Mendelian randomization analyses, and randomized clinical trials support the potential of CETP inhibition to reduce atherosclerotic cardiovascular disease (ASCVD) risk through a reduction of apolipoprotein B-containing lipoproteins. In contrast, raising high-density lipoprotein (HDL) particles, as previously hypothesized, did not contribute to ASCVD risk reduction.
Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non-human primate studies and clinical trials.
Pharmacol Res Perspect
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NewAmsterdam Pharma B.V, Naarden, The Netherlands.
Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half-life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development.
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