Acylated Spiropiperidine Derivatives for MC4R Modulation

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Solution Overview

Problem

Current weight loss treatments for obesity have limited efficacy and are associated with significant side effects, and existing treatments for sexual dysfunction, such as erectile dysfunction, have undesirable side effects and limited applicability.

Innovation Solution

Development of acylated spiropiperidine derivatives that act as selective melanocortin-4 receptor (MC4R) agonists and antagonists, which can be administered to treat obesity, diabetes, sexual dysfunction, nicotine addiction, and alcoholism, offering improved efficacy and reduced side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current weight loss treatments are used, then weight loss effect is achieved, but side effects increase and efficacy is limited

Engineering Contradiction:

Improvetreatment efficacyVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by developing novel acylated spiropiperidine derivative compounds with modified chemical structures and properties. These compounds represent a change in the pharmacological parameters of MC4R modulators, achieving improved weight loss efficacy (up to 15-20% body weight reduction) while reducing side effects compared to existing treatments like sibutramine or orlistat.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention employs composite materials by creating complex acylated spiropiperidine derivative molecules that combine multiple functional groups and structural elements. These composite chemical structures (formula I with various substituents R1-R6, X, Y, Z) provide enhanced selectivity for MC4R receptors, improving therapeutic efficacy while minimizing off-target side effects.

Inventive Principle:

Principle #40Composite materials

2Reliability

If selective MC4R agonists are developed, then treatment efficacy for obesity is improved, but drug development complexity increases

Engineering Contradiction:

Improveselectivity for MC4RVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the complex molecule into distinct functional segments: the spiropiperidine core structure, the N-acyl substituent (formula II), and various aromatic/heterocyclic groups (R1-R6). This modular segmentation allows for systematic optimization of MC4R selectivity while managing molecular complexity through structured design.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention uses local quality by introducing specific functional groups and substituents at particular positions on the molecular structure. The acyl group at the N-position, the aromatic rings, and heterocyclic groups are strategically placed to enhance MC4R binding affinity and selectivity, with each local modification contributing to overall therapeutic performance.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS8293900B2Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators

Publication Date: 2012.10.23 MERCK SHARP & DOHME LLC

AI summary

Certain novel N-acylated spiropiperidine derivatives are ligands of the human melanocortin receptor(s) and, in particular, are selective ligands of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the modulation of MC-4R, such as obesity, diabetes, nicotine addiction, alcoholism, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.