Monocyclic Amide CGRP Receptor Antagonists for Migraine

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Solution Overview

Problem

Current treatments for disorders involving CGRP, such as migraine and cluster headache, lack effective pharmacological agents that can specifically target CGRP receptors to prevent or alleviate symptoms.

Innovation Solution

Development of monocyclic amide compounds that act as CGRP receptor antagonists, which can be used in pharmaceutical compositions to treat or prevent diseases associated with CGRP, including migraine and cluster headache.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for migraine and cluster headache are used, then patients receive existing therapeutic options, but effective pharmacological agents that specifically target CGRP receptors are lacking

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidavailability of specific CGRP receptor targeting agents

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of CGRP analogs - specifically changing the peptide backbone to include non-natural amino acids, cyclic constraints, and amide bonds - to create compounds with altered binding properties that achieve selective CGRP receptor antagonism while maintaining therapeutic effectiveness for migraine and cluster headache

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite molecular structures by combining multiple functional elements: cyclic peptide frameworks, non-natural amino acid residues, amide linkages, and specific side chain configurations to produce hybrid molecules that function as selective CGRP receptor antagonists with improved pharmacological properties

Inventive Principle:

Principle #40Composite materials

2Ease of operation

If CGRP is released from cells to mediate biological actions including vasodilation, then physiological functions are performed, but pathological effects such as migraine attacks and increased vasodilation occur

Engineering Contradiction:

Improvephysiological function performanceVSAvoidheadache pain and vasodilation effects

Core Design Contradiction:

Ease of operationVSObject-generated harmful factors

Solution Approach 1:

The patent introduces monocyclic amide CGRP receptor antagonist compounds as intermediary substances that bind to CGRP receptors and block the pathological signaling pathway. These compounds act as mediators that prevent CGRP from triggering migraine attacks and excessive vasodilation while allowing normal physiological functions to continue

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent applies preliminary anti-action by administering CGRP receptor antagonist compounds before CGRP can exert its harmful effects. The antagonists pre-occupy the receptors and prevent CGRP binding, thereby blocking the initiation of migraine attacks and pathological vasodilation before they occur

Inventive Principle:

Principle #9Preliminary anti-action

Data Source

PatentUS8362005B2Monocyclic amide CGRP receptor antagonists

Publication Date: 2013.01.29 MERCK SHARP & DOHME LLC

AI summary

Compounds of formula (I): wherein variables B, m, n, J, R4, Ea, Eb, Ec, Re, Rf, RPG and Y are as described herein, which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.