Azabicyclo Hexane Derivatives for Dopamine D3 Receptor Selectivity
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Solution Overview
Problem
Current compounds targeting dopamine D3 receptors for therapeutic applications, such as treating drug dependency and antipsychotic agents, lack specificity and efficacy due to variable biological activity among stereoisomers and limited affinity for the D3 receptor compared to D2 receptors.
Innovation Solution
Development of novel compounds with a specific 'cis' disposition of substituents on a fused cyclopropane ring system, which are stereoisomerically enriched to at least 90% e.e., enhancing affinity for the dopamine D3 receptor and reducing unwanted effects on D2 receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compounds with variable stereoisomers are used, then general dopamine receptor activity is achieved, but specificity for D3 receptor and biological efficacy are reduced
Solution Approach 1:
The patent applies parameter changes by controlling the stereochemical configuration of the cyclopropane ring substituents to achieve 'cis' disposition (where both groups are on the same face of the bicyclic ring system). This specific geometric parameter change enhances affinity for the dopamine D3 receptor while reducing activity at D2 receptors, thereby improving both reliability of biological activity and receptor selectivity simultaneously.
2Reliability
If conventional dopamine D3 receptor ligands are used, then therapeutic potential is achieved, but affinity for D3 receptor compared to D2 receptor is limited
Solution Approach 1:
The patent applies local quality by introducing specific substituents at defined positions on the cyclopropane ring system with 'cis' disposition. The aryl group at position 1 and the substituent at position 3 are locally optimized to interact with specific residues in the D3 receptor binding pocket, creating local structural features that enhance D3 selectivity and reduce off-target effects on D2 receptors.
Solution Approach 2:
The patent employs asymmetry through the chiral centers created by the cyclopropane ring fusion and the specific stereochemical configuration. The asymmetric 'cis' arrangement of substituents on the bicyclic ring system creates a three-dimensional structure that selectively fits the D3 receptor binding site, improving therapeutic efficacy while minimizing unwanted interactions with D2 receptors.
Data Source
AI summary
The present invention relates to novel compounds of formula (I) or a pharmaceutically acceptable salt thereof: wherein G is selected from a group consisting of: phenyl, pyridyl, benzothiazolyl and indazolyl; p is an integer ranging from 0 to 5; R1 is independently selected from a group consisting of: halogen, hydroxy, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkanoyl and SF5; or corresponds to a group R5; each R2 is independently hydrogen or C1-4alkyl; n is 2, 3, 4 or 5; R3 is C1-4alkyl; R4 is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or 6-membered heteroaromatic group, or a 8- to 11-membered bicyclic group, any of which groups is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl and SF5; R5 is selected from a group consisting of: isoxazolyl, -CH2-N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl and 2-pyrrolidinonyl, and such a group is optionally substituted by one or two substituents selected from a group consisting of: halogen, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and C1-4alkanoyl; and when R1 corresponds to R5, p is 1; processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as modulators of dopamine D3 receptors, e.g. to treat drug dependency, as antipsychotic agents, to treat obsessive compulsive spectrum disorders, premature ejaculation or cognition impairment.