Quinoline Compounds for Selective 5-HT6 Receptor Modulation
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Solution Overview
Problem
Current quinoline compounds with affinity for the 5-HT 6 receptor lack high selectivity, leading to significant side effects due to interaction with adrenergic, histamine, and dopaminergic receptors, and have suboptimal pharmacological profiles such as low brain plasma ratio and metabolic stability.
Innovation Solution
Development of quinoline compounds of formula (I) with specific moieties that exhibit selective binding to the 5-HT 6 receptor, minimizing affinity for other receptors and enhancing pharmacological properties like bioavailability and metabolic stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If quinoline compounds with affinity for 5-HT6 receptor are used, then therapeutic effect for CNS disorders is achieved, but selectivity is low leading to side effects from interaction with other receptors
Solution Approach 1:
The patent applies local quality by introducing specific substituents at defined positions on the quinoline core structure. The R1, R2, R3, R4, R5, R6, R7, R8, Ar, A, and X parameters allow precise local modification of molecular properties to enhance 5-HT6 receptor selectivity while maintaining therapeutic activity, thereby reducing unwanted interactions with other receptors.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters including substituent types, positions, and configurations on the quinoline scaffold. This includes modifying the nature of R groups, aromatic substituents Ar, and heteroatom positions to optimize the balance between affinity for 5-HT6 receptor and selectivity against other biogenic amine receptors.
2Power
If quinoline compounds are designed for high 5-HT6 receptor affinity, then potency is improved, but pharmacological profile becomes suboptimal with low brain plasma ratio and metabolic instability
Solution Approach 1:
The patent optimizes pharmacological profile through parameter changes in molecular structure, including adjustments to lipophilicity, molecular weight, and metabolic stability parameters. The specific substituent patterns and structural features are designed to improve brain plasma ratio and metabolic stability while preserving high potency at the 5-HT6 receptor.
Data Source
AI summary
The present invention relates to novel quinoline compounds. The compounds possess valuable therapeutic properties and are particularly suitable, for treating diseases that respond to modulation of the serotonin 5-HT6 receptor. formula (I) wherein R is a moiety of the formula (R) wherein A, R1 to R4 are as defined in the claims and the specification, n is 0, 1 or 2; m is 0, 1, 2 or 3; Ra, Rb are independently selected from the group consisting of halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C(O)Raa, C(O)NRccRbb and NRccRbb; X is CH2, C(O), S, S(O) or S(O)2; which is located in the 3- or 4-position of the quinoline ring; Ar is a radical Ar1, Ar2-Ar3 or Ar2-O-Ar3, wherein Ar1, Ar2 and Ar3 are each independently selected from the group consisting of aryl or hetaryl wherein aryl or hetaryl moieties may be unsubstituted or may carry 1, 2, 3 substituents Rx, wherein and physiologically tolerated acid addition salts and the N-oxides thereof.