The invention is directed to small molecule mimetics of apolipoproteins that have an inter-helical hydrocarbon bond, which stabilizes helix formation.

Apolipoproteins facilitate the transport of lipids and cholesterol in the body. Mimetics of apolipoproteins have been used to treat cholesterol-related disorders. However, these mimetics are susceptible to degradation in biological fluids and as a result, their ability to bind cholesterol becomes diminished over time.

This invention discloses small molecule inhibitors of human 12-lipoxygenase (12-hLO). 12-lipoxygenase expression, activation, and lipid metabolites have been implicated in type 1 and type 2 diabetes, cardiovascular disease, hypertension, Alzheimer’s, and Parkinson’s disease. The development of 12-hLO inhibitors may be a potent intracellular approach to decreasing the ability of platelets to form large clots in response to vessel injury or activation of the coagulation pathway.

Prevention of cardiovascular disorders such as myocardial infarction and stroke is an area of major public health importance. Currently, several risk factors for future cardiovascular disorders have been described and are in wide clinical use in the detection of individuals at high risk. However a large number of cardiovascular disorders occur in individuals with apparently low to moderate risk profiles, thereby limiting the ability to identify such patients. Moreover, many of the risk factors require accurate gathering of clinical information.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a very rare progressive childhood disorder characterized by premature aging (progeria). Recently, the gene responsible for HGPS was identified (Eriksson M, et al. Nature 2003), and HGPS joined a group of syndromes — the laminopathies — all of which are caused by various mutations in the lamin A/C gene (LMNA). Lamin A is one of the family of proteins that is modified post-translationally by the addition of a farnesyl group.

The identification of more sensitive and specific markers of atherosclerosis that are non-invasive and cost-effective may have profound impacts on public health. One such strategy involves the detection of marker genes or their products in blood or serum. Such markers may help identify high-risk patients with subclinical atherosclerosis who may benefit from intensive primary prevention or they may help determine the activity of established disease for monitoring response to treatment, resulting in more targeted secondary prevention.