Pyrazole Derivatives Selective TAAR1 Binding
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Solution Overview
Problem
Current medications targeting central nervous system disorders often have undesirable side effects due to non-selective binding to adrenergic receptors, and there is a need for compounds that selectively target trace amine associated receptors (TAARs), particularly TAAR1, to treat conditions like depression, anxiety, and Parkinson's disease.
Innovation Solution
Development of compounds of specific formulas (IA and IB) and their pharmaceutically acceptable salts, which exhibit good affinity for TAAR1 receptors with minimal adrenergic receptor binding, allowing for selective targeting and potential treatment of various neurological and psychiatric disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compounds are designed to target adrenergic receptors for treating central nervous system disorders, then therapeutic effects are achieved, but undesirable side effects occur due to non-selective binding
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (formulas IA and IB featuring pyrazole cores with particular substituent patterns) that confer selective affinity for TAAR1 receptors over adrenergic receptors. This structural specificity ensures the compound interacts preferentially with the target receptor subtype, achieving therapeutic effects while minimizing off-target binding to adrenergic receptors that causes side effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters such as substituent types (R1-R6 groups), their positions on the pyrazole core, and stereochemical configurations to optimize receptor selectivity. By adjusting these chemical parameters, the compounds achieve high affinity for TAAR1 while maintaining low affinity for adrenergic receptors, thereby resolving the contradiction between therapeutic effectiveness and side effect profile.
2Object-affected harmful factors
If compounds bind selectively to TAAR1 receptors, then side effects are reduced, but affinity and binding strength may be compromised
Solution Approach 1:
The patent achieves selective high affinity for TAAR1 receptors through local quality by incorporating specific structural features in formulas IA and IB, including the pyrazole core with strategically positioned substituents (R1-R6 groups) that match the binding pocket characteristics of TAAR1. This localized structural optimization ensures strong binding to the target receptor while maintaining selectivity against adrenergic receptors.
Solution Approach 2:
The patent utilizes composite molecular structures combining the pyrazole core with various aromatic and aliphatic substituent groups to create compounds with optimized binding properties. These composite structures integrate multiple functional elements that collectively enhance affinity for TAAR1 while preserving selectivity, resolving the potential trade-off between binding strength and selectivity.
Data Source
AI summary
The invention relates to compounds of formula wherein R1 is hydrogen or phenyl, optionally substitutes by halogen, CN or lower alkoxy or lower alkoxy substituted by halogen; R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl or is phenyl optionally substituted by one or more substituents, selected from halogen, cyano or lower alkoxy substituted by halogen, or is pyridinyl, optionally substituted by halogen or lower alkyl substituted by halogen, or is pyrimidinyl, optionally substituted by lower alkyl substituted by halogen, or is pyrazinyl, optionally substituted by halogen, cyano or lower alkyl substituted by halogen; R4 is hydrogen, lower alkyl or phenyl; Z is a bond, -CH2- or -O-; or to a pharmaceutically suitable acid addition salt thereof. It has now been found that the compounds of formulas IA and IB have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.