Related Experiment Video
Updated: Jul 9, 2026
14:39
Bronchial Thermoplasty: A Novel Therapeutic Approach to Severe Asthma
Published on: November 4, 2010
Arylpropanolamines: selective beta3 agonists arising from strategies to mitigate phase I metabolic transformations
W N Washburn1, T W Harper, G Wu
1Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. William.Washburn@bms.com
Bioorganic & Medicinal Chemistry Letters
|May 30, 2007
Summary
Researchers developed new beta(3) agonists by modifying chemical structures to prevent unwanted side effects from metabolic N-dealkylation, leading to a potent and selective beta(3) agonist.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Metabolism
Background:
- N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines (1) are investigated as selective beta(3) agonists.
- Metabolic oxidative N-dealkylation of these compounds generates potent alpha(1) adrenergic agonists (2), complicating their therapeutic use.
Purpose of the Study:
- To summarize the structure-activity relationship (SAR) of the hepatic microsomal conversion of 1 to 2.
- To develop strategies to mitigate the N-dealkylation consequences while retaining the advantages of chemotype 1.
- To identify novel, potent, and selective beta(3) adrenergic agonists.
Main Methods:
- Analysis of SAR for hepatic microsomal N-dealkylation.
- Chemical modification of ethanolamine derivatives to propanolamines.
- Evaluation of stereochemical requirements for beta adrenergic receptor binding.
Main Results:
- Identified 4-hydroxy-3-methylsulfonanilidopropanolamines (15) as a new chemotype.
- Elucidated SAR for beta adrenergic receptor binding, including unique stereochemical requirements.
- Identified compound 15f as a potent and selective beta(3) agonist.
Conclusions:
- Strategies to mitigate N-dealkylation were successfully developed.
- Novel beta(3) agonists with improved metabolic profiles were identified.
- Compound 15f represents a promising candidate for further therapeutic development.
Related Concept Videos
01:30Adrenergic Agonists: Direct-Acting Agents
Drugs that mimic the action of endogenous catecholamines like noradrenaline and adrenaline are called adrenergic agonists or sympathomimetics. Based on their mechanism of action, sympathomimetics can be classified as direct-, indirect-, or mixed-acting sympathomimetics. Direct-acting adrenergic agonists activate adrenoceptors without affecting presynaptic neurons, making them independent of neuronal catecholamine-depleting agents like reserpine and guanethidine.
These agents can be classified...
These agents can be classified...
01:28Adrenergic Agonists: Mixed-Action Agents
Mixed-action adrenergic agonists, like ephedrine and pseudoephedrine, directly and indirectly affect adrenergic receptors. These agents stimulate adrenoceptors and indirectly release stored neurotransmitters, amplifying the adrenergic response.
Ephedrine and pseudoephedrine lack a catecholamine group, making them less susceptible to degradation by metabolic enzymes. They have increased oral bioavailability and lipophilicity, resulting in a longer duration of action. Their response is reduced by...
Ephedrine and pseudoephedrine lack a catecholamine group, making them less susceptible to degradation by metabolic enzymes. They have increased oral bioavailability and lipophilicity, resulting in a longer duration of action. Their response is reduced by...
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
01:30Adrenergic Agonists: Therapeutic Uses
Adrenergic agonists have diverse therapeutic uses across various medical conditions and emergencies.
Emergency and Intensive Care Unit (ICU) applications: Pressor agents increase blood pressure, heart rate, and contractility in shock and organ failure situations. Dopamine can induce vasodilation and stimulate adrenoceptors. Endogenous catecholamines are effective in treating cardiogenic shock. α2-agonists like clonidine can reverse anesthesia-induced hypertension.
Allergies and anaphylaxis:...
Emergency and Intensive Care Unit (ICU) applications: Pressor agents increase blood pressure, heart rate, and contractility in shock and organ failure situations. Dopamine can induce vasodilation and stimulate adrenoceptors. Endogenous catecholamines are effective in treating cardiogenic shock. α2-agonists like clonidine can reverse anesthesia-induced hypertension.
Allergies and anaphylaxis:...
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...
01:23Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists
Prostacyclin receptor agonists are a class of therapeutic agents integral to managing pulmonary arterial hypertension (PAH). These drugs operate by mimicking the action of prostaglandin I2, or PGI2, a naturally occurring compound in the body.
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...