Medicinal Chemistry

Pharmacological Modulators of Molecular Clock and their Therapeutic Potentials in Circadian Rhythm-Related Diseases

Abstract

Gi Hoon Son, Sooyoung Chung, Victor D Ramirez and Kyungjin Kim

Circadian rhythms regulate a wide range of biological processes and play a fundamental role in mammalian behavior, physiology, and metabolism. The hierarchically organized circadian timing system in mammals, with a master pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus and subsidiary oscillators in extra-SCN brain regions and peripheral tissues, mediates periodicities in physiological processes. It has been well recognized that disruption or misalignment of the intrinsic rhythms leads to diverse pathological states. Since mammalian circadian clock genes were first identified in the 1990’s, genetic and biochemical approaches have uncovered the molecular bases of the cell-autonomous and self-sustainable rhythms that are generated by two interlocking feedback loops of clock proteins. With our understanding of key features underlying the overt circadian rhythm and physiological outputs, it has emerged that pharmacological control of the circadian clock may provide a novel therapeutic strategy to treat a variety of circadian rhythm-related human diseases such as neuropsychiatric, metabolic, cardiovascular, and immune/inflammatory diseases, and even cancer. Pharmaceutical approaches to circadian clock may involve either development of drugs to treat such circadian-related disorders or combinational uses with existing therapeutic strategies to improve their therapeutic efficacy via the intrinsic clock-dependent mechanisms. In this review, we will focus on recent progress in discovery of small molecule chemical compounds that can pharmacologically modulate molecular circadian clock and their potential to be developed into therapeutic drugs.