BK channel modulators: A comprehensive overview

The large Ca2+-activated K+ channel (BK channel) reflects per excellence the dilemma of the molecular target driven drug discovery process. Significant experimental evidence suggests that the BK channels play a pivotal and specific role in many pathophysiological conditions supporting the notion that the channel represents an innovative and promising drug target. However, after more than ten years of intense research effort both in academia and industry, scientists have yet to witness the approval of a single BK channel modulator for clinical use. On the contrary, three BK openers that were progressed to clinical development have recently been discontinued (NS8, BMS204352 and TA1702) and, at the present time, only one drug candidate targeting BK channels (andolast) remains in the early phases of clinical development. Since biological studies keep strengthening the concept of BK channels as a potentially attractive target, the design and synthesis of potent and selective BK modulators continue based on novel chemical ideas. A comprehensive overview of BK channel modulators is therefore timely and important to the current medicinal chemist for review, summary, and classification of the multitude of chemical entities claimed to be BK-modulating agents. Such chemical entities are, herein, classified by both origin and chemical structure in 1) Endogenous BK channel modulators and structural analogues 2) Naturally-occurring BK channel inhibitors and blockers 3) Synthetic BK channel inhibitors and blockers 4) Marketed and/or investigational drugs with BK-modulating side properties and structural analogues 5) Naturally-occurring BK channel openers and structural analogues 6) Synthetic BK channel openers. This review is intended to provide readers with current opinion on the BK channel as a drug target, the chemical structures of BK channel modulators, the structural and chemical features involved in the BK channel modulating activity and, where and when possible, with highlights of structure -activity relationships.