Selective Amide Compounds for CNS Disorders
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Solution Overview
Problem
Nicotinic compounds used for treating CNS disorders often have undesirable side effects due to stimulation of muscle and ganglionic receptors, leading to significant cardiovascular and skeletal muscle effects.
Innovation Solution
Development of amide compounds formed from heteroaryl carboxylic acids and diazabicycloalkanes, specifically 3,7-diazabicyclo[3.3.0]octane and 3,7-diazabicyclo[3.3.1]nonane, which selectively bind to α4β2 nicotinic acetylcholine receptors in the CNS, reducing side effects by minimizing activity at muscle and ganglionic receptor subtypes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nicotinic compounds are used to treat CNS disorders, then therapeutic effect on CNS is improved, but side effects from muscle and ganglionic receptor stimulation increase
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (amides of diazabicycloalkanes with particular stereochemistry) that selectively interact with CNS nicotinic receptor subtypes. This structural specificity enables the compound to produce therapeutic effects in the CNS while avoiding activation of muscle and ganglionic receptors, thereby resolving the contradiction between efficacy and side effects.
Solution Approach 2:
The patent employs parameter changes by optimizing specific molecular parameters including stereochemical configuration, substituent patterns, and structural features of the diazabicycloalkane amide compounds. These parameter optimizations tune the receptor selectivity profile to enhance CNS penetration and binding while reducing affinity for peripheral nicotinic receptors, thus achieving therapeutic benefit without significant side effects.
2Adaptability or versatility
If nicotinic compounds stimulate muscle and ganglionic receptors, then broader receptor coverage is achieved, but cardiovascular and skeletal muscle effects worsen
Solution Approach 1:
The patent applies segmentation by dividing the nicotinic receptor family into distinct subtype categories (CNS versus peripheral receptors) and designing compounds that selectively target only the CNS subtype. This selective segmentation allows the compound to achieve therapeutic coverage in the CNS while deliberately excluding interaction with muscle and ganglionic receptors, avoiding harmful cardiovascular and skeletal muscle effects.
Data Source
AI summary
Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are amide compounds which can be prepared from certain heteroaryl carboxylic acids and certain diazabicycloalkanes. The compounds exhibit selectivity for, and bind with high affinity to, neuronal nicotinic receptors of the α4β2 subtype in the central nervous system (CNS). The compounds and compositions can be used to treat and/or prevent a wide variety of conditions or disorders, particularly CNS disorders. The compounds can: (i) alter the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects, and (iii) when employed in effective amounts, not result in appreciable adverse side effects (e.g. side effects such as significant increases in blood pressure and heart rate, significant negative effects upon the gastrointestinal tract, and significant effects upon skeletal muscle).