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Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability
David A Perrey1, Ann M Decker1, Yanan Zhang1
1Research Triangle Institute , Research Triangle Park , North Carolina 27709 , United States.
Abstract:
Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogues where the 7-position substituents known to favor OX1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies. Compound 44 with lower lipophilicity (clogP = 3.07) displayed excellent OX1 potency ( Ke = 5.7 nM) and selectivity (>1,760-fold over OX2) in calcium mobilization assays. In preliminary ADME studies, 44 showed excellent kinetic solubility (>200 μM), good CNS permeability ( Papp = 14.7 × 10-6 cm/sec in MDCK assay), and low drug efflux (efflux ratio = 3.3).
Insights
New drug candidates targeting the orexin-1 receptor show promise for treating addiction. Compound 44 demonstrates high potency and selectivity, with improved drug-like properties for potential therapeutic applications.
Area of Science:
- Neuroscience
- Pharmacology
- Medicinal Chemistry
Background:
- Orexins, hypothalamic neuropeptides, are implicated in motivating addictive behaviors.
- Orexin-1 receptor (OX1R) antagonists are a potential therapeutic strategy for drug addiction.
- Previous OX1R antagonists based on the tetrahydroisoquinoline scaffold had high lipophilicity and poor solubility.
Purpose of the Study:
- To design and synthesize novel tetrahydroisoquinoline-based OX1R antagonists with improved physicochemical properties.
- To identify compounds with enhanced solubility and reduced lipophilicity while maintaining OX1R potency and selectivity.
Main Methods:
- Synthesis of a series of tetrahydroisoquinoline analogues with modifications at the 1-position.
- Evaluation of OX1R antagonist potency and selectivity using calcium mobilization assays.
- Assessment of lipophilicity (clogP), kinetic solubility, CNS permeability, and drug efflux (ADME studies).
Main Results:
- Compound 44 exhibited low lipophilicity (clogP = 3.07) and high OX1R potency (Ke = 5.7 nM).
- Compound 44 demonstrated excellent selectivity (>1,760-fold over OX2).
- Preliminary ADME studies showed excellent kinetic solubility (>200 μM), good CNS permeability, and low drug efflux for compound 44.
Conclusions:
- Modification of the tetrahydroisoquinoline scaffold at the 1-position led to improved drug-like properties.
- Compound 44 represents a promising lead candidate for the development of novel therapeutics for addiction.
- Further investigation of compound 44 is warranted for its potential in treating substance use disorders.
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