Abstract
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.
Keywords: BK channel modulators, BK channel openers, BK channel blockers, BK channels, Maxi-K channels, BKCa, KCa1.1.
Current Medicinal Chemistry
Title: BK Channel Modulators: A Comprehensive Overview
Volume: 15 Issue: 11
Author(s): Antonio Nardi and Soren-Peter Olesen
Affiliation:
Keywords: BK channel modulators, BK channel openers, BK channel blockers, BK channels, Maxi-K channels, BKCa, KCa1.1.
Abstract: 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.
Export Options
About this article
Cite this article as:
Nardi Antonio and Olesen Soren-Peter, BK Channel Modulators: A Comprehensive Overview, Current Medicinal Chemistry 2008; 15 (11) . https://dx.doi.org/10.2174/092986708784221412
DOI https://dx.doi.org/10.2174/092986708784221412 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
A Single Pill to Treat Postmenopausal Hypertension? Not Yet
Current Topics in Medicinal Chemistry Oxidized-LDL and Paraoxonase-1 As Biomarkers of Coronary Artery Disease in Patients with Sleep-Disordered Breathing
Current Medicinal Chemistry Does It Make Sense that Diabetes is Reciprocally Associated with Periodontal Disease?
Endocrine, Metabolic & Immune Disorders - Drug Targets Oxidative Stress-Induced Ischemic Heart Disease: Protection by Antioxidants
Current Medicinal Chemistry Targeting miRNAs for Drug Discovery: A New Paradigm
Current Molecular Medicine Nanotechnology: A Novel Approach for Drug Development in Health Care System
Current Nanomaterials Statins and epilepsy: preclinical studies, clinical trials and statin-anticonvulsant drug interactions
Current Drug Targets Tailored Angiogenesis Inhibition in Cancer Therapy: Respecting the Heart to Improve the Net Outcome
Current Signal Transduction Therapy Current Updates on Therapeutic Advances in the Management of Cardiovascular Diseases
Current Pharmaceutical Design Clinical Significance of the Cardio-Ankle Vascular Index (CAVI) in Hypertension
Current Hypertension Reviews Nutritional and therapeutic approaches to modulate NADPH oxidase-derived ROS signaling in platelets.
Current Pharmaceutical Design Detection and Treatment of Alcohol-Induced Hypertension
Current Hypertension Reviews A Review of the Characteristics, Properties and Methods for Quantification of Roxithromycin
Current Pharmaceutical Analysis Use of Paediatric Xylometazoline Nasal Drop is not a Child’s Play in Hypertensive Patients on Bisoprolol: A Case Report
Current Drug Safety New Trends in Anti-Atherosclerotic Agents
Current Medicinal Chemistry Chemokines in Cardiovascular Remodeling: Clinical and Therapeutic Implications
Current Molecular Medicine The Many Faces of Glutathione Transferase Pi
Current Molecular Medicine Physical Activity and Diabetic Cardiomyopathy: Myocardial Adaptation Depending on Exercise Load
Current Diabetes Reviews Nursing Assessment, Education, and Care of Extremely Premature Neonates with Patent Ductus Arteriosus
Current Pediatric Reviews Editorial [Hot topic: Developing New Anti-Cancer Drugs (Guest Editor: Ricardo De Souza Pereira)]
Recent Patents on Anti-Cancer Drug Discovery