Pharmacophore development for corticotropin-releasing hormone: New insights into inhibitor activity

Corticotropin-releasing hormone (CRH) is an endogenous 41-amino acid peptid e involved in a wide ranging series of systems including the brain, the coo rdination of the body's overall response to stress, and more recently as a crucial initiator in the onset of labor, also known as the placental clock. Although more physiological data on CRH is emerging shedding more light on the processes involved and their integration, the mode of action of the ho rmone and the postulated binding site(s) remain unknown. Recently, a number of small-molecular-weight ligands have emerged as potent antagonists but, as therapeutics, suffer from a lack of solubility. Additionally, despite a number of exhaustively large patents, the lack of structural diversity with these antagonists has enabled little scope for comprehensive and wide rang ing studies into the structure of the binding sites of this hormone. As par t of a program investigating new, structurally diverse antagonists and agon ists of CRH, we have developed a preliminary pharmacophore based on the kno wn small-molecular-weight ligands as an initial step in our program. This p harmacophore was validated by comparison with some of the compounds we post ulated to be active.