Related Experiment Video
Updated: Jun 22, 2026
10:07
High-throughput Screening for Small-molecule Modulators of Inward Rectifier Potassium Channels
Published on: January 27, 2013
Novel small molecule bradykinin B2 receptor antagonists
Christoph Gibson1, Karsten Schnatbaum, Jochen R Pfeifer
1Department of Medicinal Chemistry, Jerini AG, Berlin D-10115, Germany. christoph.gibson@jerini.com
Journal of Medicinal Chemistry
|June 26, 2009
Summary
Researchers developed potent bradykinin B(2) receptor antagonists for hereditary angioedema (HAE). The optimized compound, 52e (JSM10292), is orally available and shows promising therapeutic properties.
Area of Science:
- Pharmacology
- Medicinal Chemistry
Background:
- The bradykinin B(2) receptor plays a crucial role in hereditary angioedema (HAE) and other conditions.
- Blockade of this receptor offers therapeutic potential.
Purpose of the Study:
- To develop highly potent bradykinin B(2) receptor antagonists with a molecular weight around 500 g/mol.
- To identify orally available antagonists with optimized drug-like properties.
Main Methods:
- Stripped down known quinoline-based antagonists to identify the minimum pharmacophore (motif 53).
- Performed targeted modifications and structure-activity relationship (SAR) studies.
- Optimized microsomal stability and cytochrome P450 inhibition.
Main Results:
- Identified motif 53 as the minimal pharmacophore.
- Developed a highly water-soluble lead compound (8a).
- Discovered potent B(2) receptor antagonists, including 52e (JSM10292), with improved stability and low P450 inhibition.
Conclusions:
- Developed highly potent, orally available bradykinin B(2) receptor antagonists.
- Compound 52e (JSM10292) exhibits excellent overall properties for potential HAE therapy.
- The identified pharmacophore and optimization strategies are valuable for future drug discovery.
Related Concept Videos
01:25Adrenergic Antagonists: Chemistry and Classification of β-Receptor Blockers
β-adrenergic antagonists, or β-blockers, modulate the sympathetic nervous system by targeting β-adrenoceptors and inhibiting catecholamine-mediated sympathetic responses. β-blockers differ in their adrenoceptor subtype affinity, lipophilicity, and α-blocking capabilities. The history of β-blocker development began with the prototype, dichloroisoprenaline, which exhibited partial agonist activity. As a result, propranolol was developed as a pure antagonist but nonselective agent, paving the way...
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
The activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) contributes to cardiac remodeling, and inhibiting the RAAS is a pharmacological target in heart failure management. As a result, neurohumoral modulation is a crucial treatment principle for managing heart failure. This approach involves using medications like ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, mineralocorticoid receptor antagonists (MRAs), and neutral...
01:17Adrenergic Antagonists: Chemistry and Classification of ɑ-Receptor Blockers
Adrenergic antagonists, or sympatholytics, inhibit adrenoceptor activation driven by catecholamines or agonists. Based on their adrenoceptor specificity, adrenergic blockers can be categorized into two primary groups: α-adrenergic blockers (α-blockers) and β-adrenergic blockers (β-blockers). α-blockers interact with α1 and α2 subtypes of α-adrenoceptors.
Nonselective α-blockers: Nonselective α-blockers contain haloalkylamine or imidazoline moieties. Phenoxybenzamine, with a haloalkylamine...
Nonselective α-blockers: Nonselective α-blockers contain haloalkylamine or imidazoline moieties. Phenoxybenzamine, with a haloalkylamine...
01:30Antihypertensive Drugs: Angiotensin II Receptor Blockers
In the renin-angiotensin-aldosterone system, a hormone called angiotensin II plays a crucial role. It binds to the AT1 receptors in vascular smooth muscles coupled with Gq proteins. The activation of these receptors activates an enzyme called phospholipase C, which releases two molecules: inositol trisphosphate and diacylglycerol. These molecules cause a chain reaction that leads to the phosphorylation of myosin light chains and promotes interaction between actin and myosin, leading to smooth...
01:24Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers
Adrenergic stimulation generally impacts cardiac rate and rhythm. Specifically, stimulation of the β-adrenoceptors triggers an increase in intracellular calcium ion influx and pacemaker currents, which may cause arrhythmias. Catecholamines like adrenaline also demonstrate β2-adrenoceptor-mediated hypokalemia, impacting cardiac action potential and disrupting the normal cardiac rhythm. Class II antiarrhythmic drugs are β-adrenoceptor antagonists or β-blockers, which indirectly block calcium...
01:18Treatment for Pulmonary Arterial Hypertension: Endothelin Receptor Antagonists
Endothelins (ETs) are potent vasoactive peptides critical in the human body's various physiological and pathological processes. One of the most promising therapeutic strategies for treating pulmonary arterial hypertension (PAH) involves counteracting the effects of these endothelins using a class of drugs known as endothelin receptor antagonists.
ETs are synthesized through a complex sequence of enzymatic steps, primarily involving an enzyme referred to as endothelin-converting enzyme (ECE). Of...
ETs are synthesized through a complex sequence of enzymatic steps, primarily involving an enzyme referred to as endothelin-converting enzyme (ECE). Of...