Vitamin D Receptor Agonists for CKD Cardiovascular Complications
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Solution Overview
Problem
Current vitamin D receptor agonists are limited in their ability to effectively target and treat cardiovascular complications and disease progression in chronic kidney disease patients, particularly endothelial dysfunction and proteinuria, without causing hypercalcemia.
Innovation Solution
Development of compounds of Formula (I), which include specific structural modifications such as R1=CH2 or a cyclopropyl group, R4 and R5 being H, hydroxyl, or halo, and R6 being optionally substituted alkyl or aryl, with X as oxygen or sulfur, to activate the vitamin D receptor and modulate gene expression, thereby treating disorders like endothelial dysfunction and proteinuria without elevating serum calcium levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If calcitriol or conventional vitamin D analogs are used to treat cardiovascular complications and CKD disease progression, then VDR activation and therapeutic effects are achieved, but hypercalcemia is caused
Solution Approach 1:
The patent applies local quality by modifying specific regions of the vitamin D molecule (A-ring and side chain) to create compounds with differentiated properties. Formula (I) compounds have specific substitutions at positions R1, R4, R5, and R6 that locally alter molecular interactions with VDR and calcium metabolism pathways, achieving cardiovascular and renal protection without systemic hypercalcemia
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of vitamin D analogs including substitution types (halo, hydroxyl, alkyl), positions (R1-R6), and stereochemistry. These parameter modifications tune the compounds' affinity for VDR versus their effect on calcium homeostasis, decoupling therapeutic efficacy from hypercalcemic side effects
2Reliability
If existing vitamin D analogs are used to target endothelial dysfunction and proteinuria, then some therapeutic effects are achieved, but potency and selectivity are insufficient
Solution Approach 1:
The patent applies segmentation by dividing the vitamin D molecule into distinct functional regions (A-ring with R1-R6 substituents, side chain with R7-R10 substituents) that can be independently optimized. This allows separate tuning of VDR binding affinity, calcium regulatory effects, and cardiovascular/renal protective activities
Solution Approach 2:
The patent employs asymmetry through specific chiral centers and non-symmetric substitution patterns in Formula (I). The asymmetric structure at C-25 and selective substitution patterns create compounds with enhanced stereoselectivity for VDR activation and improved potency for targeting endothelial dysfunction and proteinuria
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds effectively induce CYP24A1 and VDR expression, improve endothelial function, reduce left ventricular hypertrophy, and decrease proteinuria in CKD models, demonstrating therapeutic potential for cardiovascular complications without causing hypercalcemia.
Implementation Method 1
The compounds effectively induce CYP24A1 and VDR expression, improve endothelial function, reduce left ventricular hypertrophy, and decrease proteinuria in CKD models
Data Source
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AI summary
Disclosed is a compound of Formula (I), in which R1, R2, R3, R4, R5, R6, X, and a are defined herein, or a pharmaceutically acceptable salt thereof. Also disclosed are a pharmaceutical composition comprising a compound or salt therof of Formula (I) and a method of treating a disease which benefits from the modulation of the vitamin D receptor, such as a bone disorder, cardiovascular disease, a cardiovascular complication associated with renal disease, endothelial dysfunction, hyperparathyroidism, hypocalcemia, an immune disorder, left ventricular hypertrophy, a proliferative disease, proteinuria, renal disease, and thrombosis.