Cis-5-(hydroxymethyl)morpholine-2-carboxamides for SSTR4 Agonism
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Solution Overview
Problem
Current SSTR4 agonists, such as those disclosed in EP3045448 and WO2016075240, exhibit reduced potency and poor brain availability due to trans-hydroxymethyl substituents and poor metabolic stability, limiting their effectiveness in treating neurological and psychiatric disorders.
Innovation Solution
Development of (2S,5R)-5-(hydroxymethyl)morpholine-2-carboxamide derivatives with a cis-oriented hydroxymethyl substituent, which demonstrate higher potency, improved brain penetration, and enhanced metabolic stability, making them effective SSTR4 agonists for medicinal use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If trans-hydroxymethyl substituents are used in SSTR4 agonists, then the compounds can be synthesized, but their potency is reduced and brain availability is poor
Solution Approach 1:
The patent changes the stereochemical parameter of the hydroxymethyl substituent from trans to cis configuration. This parameter change fundamentally alters the spatial arrangement of the molecule, enabling it to properly interact with the SSTR4 receptor binding site, thereby restoring and enhancing potency while improving brain availability.
Solution Approach 2:
The invention introduces asymmetric cis-configured hydroxymethyl groups at specific positions on the morpholine ring. This asymmetry creates a three-dimensional molecular shape that complements the chiral binding site of SSTR4, improving receptor affinity and biological activity compared to symmetric or trans-configured analogs.
2Reliability
If current SSTR4 agonists are used, then they can treat neurological disorders, but their metabolic stability is poor limiting their effectiveness
Solution Approach 1:
The patent modifies the metabolic stability parameter by introducing the cis-hydroxymethyl substituent configuration and specific molecular scaffolds. These structural changes protect the molecule from metabolic degradation while maintaining its biological activity, thereby extending half-life and improving overall effectiveness in treating neurological and psychiatric disorders.
3Quantity of substance
If higher potency SSTR4 agonists are developed, then lower doses can be used, but the complexity of achieving both high potency and good brain penetration increases
Solution Approach 1:
The patent applies local quality by introducing the cis-hydroxymethyl substituent at specific localized positions on the morpholine ring rather than modifying the entire molecule. This targeted local modification achieves high potency and brain penetration without requiring complex overall molecular structures, simplifying synthesis and development.
Data Source
AI summary
The present disclosure provides cis-5-(hydroxymethyl)morpholine-2-carboxamides that are agonists of somatostatin receptor 4 (SSTR4), and are therefore useful for the treatment of diseases or medical conditions associated with SSTR4. Also provided are pharmaceutical compositions containing the same, and processes for preparing said compounds.