Constrained Bicyclic CGRP Antagonists Avoiding Cardiovascular Risks

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Solution Overview

Problem

Current treatments for migraine and other conditions associated with excessive calcitonin gene-related peptide (CGRP) receptor activation, such as migraines, lack effective non-vasoconstrictive options due to cardiovascular liabilities of existing therapies like triptans.

Innovation Solution

Development of compounds of Formula I, which act as CGRP antagonists, inhibiting the CGRP receptor to modulate peptide levels and alleviate associated conditions without causing vasoconstriction.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If vasoconstrictive treatments like triptans are used to treat migraine, then headache relief is achieved, but cardiovascular liabilities occur

Engineering Contradiction:

Improveheadache relief effectivenessVSAvoidcardiovascular liabilities

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces CGRP receptor antagonists as an intermediary mechanism to treat migraine. Instead of directly causing vasoconstriction (triptans), the compounds block CGRP receptor activation, which indirectly achieves headache relief by inhibiting the neurogenic inflammation and vasodilation pathways involved in migraine pathophysiology. This intermediary approach provides therapeutic efficacy while avoiding direct cardiovascular side effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent replaces the mechanical/physiological mechanism of direct vasoconstriction with a biochemical mechanism of receptor antagonism. The small molecule compounds (I) and (II) act as pharmacological blockers at the CGRP receptor level, substituting the direct vascular mechanical effect of triptans with a targeted molecular interaction that achieves similar therapeutic outcomes without the harmful vasoconstrictive side effects.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If peptide antagonists like CGRP(8-37) are used to block CGRP receptors, then migraine relief is achieved, but the treatments have limitations in efficacy and selectivity

Engineering Contradiction:

ImproveCGRP receptor blockade efficacyVSAvoidspecies selectivity and affinity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by modifying the molecular structure from peptide-based (CGRP(8-37)) to small molecule compounds with specific structural features (Formula I and II). This structural parameter change enables optimization of binding affinity and selectivity for human CGRP receptors. The small molecule design allows for precise tuning of pharmacokinetic and pharmacodynamic parameters to achieve better species selectivity and receptor affinity compared to peptide antagonists.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP2013213B1Constrained compounds as CGRP-receptor antagonists

Publication Date: 2011.07.27 BRISTOL MYERS SQUIBB CO

AI summary

The invention encompasses constrained bicyclic and tricyclic CGRP-receptor antagonists, methods for identifying them, pharmaceutical compositions comprising them, and methods for their use in therapy for treatment of migraine and other headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors. Formula (I).