Key result
Compound 7, a novel indoline-based CETP inhibitor, displayed potent in vitro CETP inhibition and dose-dependent efficacy in elevating HDL-cholesterol in a transgenic mouse model.
Why the study?
Does the novel indoline CETP inhibitor compound 7 improve CETP inhibition and HDL elevation compared to vehicle in preclinical models?
Does the novel indoline CETP inhibitor compound 7 improve CETP inhibition and HDL elevation compared to vehicle in preclinical models?
Structure-guided design led to the discovery of a novel indoline CETP inhibitor (compound 7) with potent in vitro activity, favorable pharmacokinetics, and in vivo efficacy in elevating HDL-C.
Hypothesis-generating for indoline CETP inhibitors; human trials needed before any clinical consideration.
Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from (1)H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.
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Wilson et al. (2016) conducted a letter in Cardiovascular disease (preclinical). Compound 7 (indoline CETP inhibitor) vs. Vehicle was evaluated on In vitro CETP inhibition (IC50) and in vivo HDL-cholesterol elevation. Compound 7, a novel indoline-based CETP inhibitor, displayed potent in vitro CETP inhibition and dose-dependent efficacy in elevating HDL-cholesterol in a transgenic mouse model.
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