Acylguanidine Derivatives for 5-HT5A Receptor Modulation
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Solution Overview
Problem
Current compounds for treating or preventing dementia and schizophrenia do not effectively modulate the 5-HT5A receptor, particularly lacking structures where the guanidine is bonded to a bicyclic nitrogen-containing ring via a carbonyl group.
Innovation Solution
Development of acylguanidine derivatives with a quinoline or isoquinoline structure, where the guanidine is bonded to one ring via a carbonyl group, exhibiting potent 5-HT5A receptor modulating actions and excellent pharmacological effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compounds with existing structures (bicyclic acylguanidine, tricyclic acylguanidine, quinoline derivatives) are used, then some 5-HT5A receptor affinity is achieved, but potent modulating action is not obtained due to lack of specific structural features
Solution Approach 1:
The patent applies parameter changes by modifying the molecular structure parameters - specifically introducing the carbonyl group between the guanidine and bicyclic nitrogen-containing ring, and positioning a cyclic group on the other ring. This structural parameter modification transforms existing compounds with weak activity into potent 5-HT5A receptor modulators.
Solution Approach 2:
The invention creates a composite molecular structure by combining multiple functional elements: guanidine group, carbonyl group, bicyclic nitrogen-containing ring, and cyclic group. This composite structure integrates the advantages of previously reported structures (bicyclic acylguanidine, tricyclic acylguanidine, quinoline derivatives) while adding the critical carbonyl linkage to achieve potent receptor modulation.
2Reliability
If new compound structures are developed to improve 5-HT5A receptor modulation, then treatment efficacy for dementia and schizophrenia is enhanced, but metabolic stability and safety may be compromised
Solution Approach 1:
The patent applies local quality by making specific localized modifications to the molecular structure - adding the carbonyl group at a specific position and placing cyclic groups at specific locations on the bicyclic ring system. These localized structural features enhance receptor binding and modulation while maintaining overall metabolic stability and safety of the compound.
Data Source
AI summary
[Object] An excellent agent for preventing or treating dementia, schizophrenia, and the like, based on serotonin 5-HT5A receptor modulating action, is provided.[Means for Solution] It was confirmed that acylguanidine derivatives (the following formula I; any one of Z1, Z2, Z3, Z4 and Z5 is nitrogen atom, and the others are carbon atoms) which have the characteristic structure in which the guanidine is bonded to one ring of the quinoline or isoquinoline via a carbonyl group, and a cyclic group is bonded to the other ring, exhibit potent 5-HT5A receptor modulating actions and excellent pharmacological actions based on the 5-HT5A receptor modulating action, and thus can be excellent agents for preventing or treating dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder. Thus, the present invention has been completed.