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Adrenergic Agonists: Chemistry and Structure-Activity Relationship01:16

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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.
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Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
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Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:22

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Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
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Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
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Direct alkylation of ammonia produces polyalkylated amines, along with a quaternary ammonium salt. To exclusively prepare primary amines, the azide synthesis method can be used.
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Direct alkylation is not a suitable method for synthesizing amines because it produces polyalkylated products. Gabriel synthesis is the most preferred method to exclusively make primary amines. The method uses phthalimide, which contains a protected form of nitrogen that participates in alkylation only once to predominantly give primary amines.
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Design and preparation of N-linked hydroxypyridine-based APJ agonists.

Jeremy M Richter1, J Alex Bates1, Peter Gargalovic1

  • 1Bristol-Myers Squibb Research & Early Development, Princeton, NJ 08540, USA.

Bioorganic & Medicinal Chemistry Letters
|July 11, 2022
PubMed
Summary

Novel N-linked apelin receptor (APJ) agonists were designed to improve metabolic stability. These compounds avoid problematic metabolite formation, offering a promising new therapeutic avenue for heart failure treatments.

Keywords:
APJApelinHeart failureHydroxypyridineSmall molecule

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Area of Science:

  • Cardiovascular Pharmacology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Apelin receptor (APJ) agonism shows therapeutic potential in heart failure models.
  • Previous APJ agonists exhibited metabolic liabilities, forming undesired atropisomer metabolites.
  • Compound 4 demonstrated APJ agonist activity but underwent metabolic mono-demethylation.

Purpose of the Study:

  • To design and optimize novel N-linked APJ agonists.
  • To enhance metabolic stability and improve pharmacokinetic profiles.
  • To develop compounds that circumvent problematic mono-demethylation cleavage.

Main Methods:

  • Structure-based drug design and medicinal chemistry optimization.
  • Synthesis of a novel series of N-linked APJ agonists.
  • In vitro and in vivo evaluation of compound potency, metabolic stability, and pharmacokinetic properties in rats.

Main Results:

  • Successful design and synthesis of a new class of N-linked APJ agonists.
  • Achieved good potency and significant improvements in metabolic stability.
  • Demonstrated favorable rat pharmacokinetic profiles.
  • Confirmed the inability of these novel compounds to undergo mono-demethylation cleavage.

Conclusions:

  • The novel N-linked APJ agonists possess desirable drug-like properties, including enhanced metabolic stability.
  • These compounds represent a promising advancement over previous APJ agonists due to their improved metabolic profile.
  • This optimized series offers a potential new therapeutic strategy for managing heart failure.