Calcimimetic Urea Compounds for PTH Secretion Inhibition
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Solution Overview
Problem
Current calcimimetic compounds are inadequate in effectively regulating extracellular calcium ion concentration, particularly in reducing or inhibiting parathyroid hormone (PTH) secretion, which is crucial for maintaining calcium homeostasis and treating conditions like osteoporosis and hyperparathyroidism.
Innovation Solution
Development of specific calcimimetic compounds represented by a general structure, including various aryl and heteroaryl groups, which interact with the calcium sensing receptor (CaSR) to modulate its activity, thereby reducing PTH secretion and treating associated bone disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing calcimimetic compounds are used, then calcium receptor activity is modulated, but the effectiveness in reducing PTH secretion is inadequate
Solution Approach 1:
The patent applies parameter changes by systematically varying key molecular parameters including the aryl group substitutions (R1 and R2), the linker structure (Z and p), and the basic amine portion (R6-R12) to optimize calcimimetic activity. Specific substitutions such as fluorine atoms, chlorine atoms, hydroxyl groups, and various alkyl groups are introduced at different positions to enhance PTH secretion inhibition while maintaining acceptable molecular complexity
Solution Approach 2:
The patent employs composite molecular structures combining multiple functional moieties: aromatic rings (phenyl, pyridinyl, thienyl), heterocyclic groups (thiazolyl, oxazolyl, imidazolyl), and basic amine chains. These composite structures integrate different chemical functionalities to achieve synergistic effects in calcium receptor modulation and PTH secretion reduction
2Reliability
If millimolar concentrations of agonists are required to stimulate the calcium receptor, then receptor activation occurs, but the therapeutic efficiency is reduced
Solution Approach 1:
The patent changes the concentration parameter by designing compounds that achieve effective calcium receptor modulation at lower concentrations than existing calcimimetics. The optimized molecular structures with specific aryl substitutions and basic amine chains demonstrate enhanced potency, reducing the required therapeutic dose while maintaining reliable receptor activation and PTH secretion inhibition
3Reliability
If various substituent groups are introduced to enhance calcimimetic activity, then PTH secretion inhibition is improved, but synthesis complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the calcimimetic molecule into distinct functional segments: the aryl group portion (R1-R5), the linker region (Z and p), and the basic amine chain (R6-R12). Each segment can be independently synthesized and then assembled through standard coupling reactions, simplifying the overall manufacturing process while allowing optimization of PTH secretion inhibition through systematic variation of each segment
Solution Approach 2:
The patent employs universal building blocks that can serve multiple functions. For example, the aryl groups with various substitutions (fluorine, chlorine, hydroxyl, alkyl) can provide both structural stability and enhanced receptor binding affinity. The basic amine chains with different lengths and substitutions can simultaneously provide solubility, receptor interaction, and pharmacokinetic properties, reducing the need for separate optimization steps
Data Source
AI summary
The present invention relates generally to compounds represented in Formula I, pharmaceutical compositions comprising them and methods of treating of diseases or disorders related to the function of the calcium sensing receptor. The invention also relates to processes for making such compounds and to intermediates useful in these processes.