Selective Urea Compounds for BPH Treatment
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Solution Overview
Problem
Current α1-AR antagonists for treating benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) have significant cardiovascular side effects and do not effectively target α1d-ARs, leading to undesirable symptoms such as dizziness, postural hypotension, and ejaculatory dysfunction, while also being contraindicated for use with PDE inhibitors.
Innovation Solution
Development of substituted [4-(4-phenyl-piperazin-1-yl)-cyclohexyl]-urea compounds that selectively modulate α1a/α1d adrenergic receptors with minimal interaction with α1b receptors, reducing cardiovascular side effects and allowing concurrent use with PDE inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective α1-AR antagonists are used to treat BPH and LUTS, then obstructive symptoms are relieved, but cardiovascular side effects occur including dizziness, postural hypotension, and ejaculatory dysfunction
Solution Approach 1:
The patent segments the α1-AR receptor system into three distinct subtypes (α1a, α1b, α1d) and designs antagonists that selectively target specific subtypes. The compounds of Formula (I) are engineered to preferentially bind to α1a and/or α1d receptors while having minimal affinity for α1b receptors, thereby segmenting the therapeutic effect from cardiovascular side effects.
Solution Approach 2:
The patent applies local quality by creating receptor-subtype-specific antagonistic activity. The compounds exhibit different binding affinities for different α1-AR subtypes, with selective antagonism at α1a and/or α1d receptors in the prostate and lower urinary tract, while sparing α1b receptors in vascular smooth muscle, thus providing localized therapeutic effect without systemic cardiovascular harm.
2Object-affected harmful factors
If selective α1a-AR antagonists are used, then cardiovascular side effects are reduced, but α1d-ARs are not effectively targeted, leaving some LUTS symptoms untreated
Solution Approach 1:
The patent merges the therapeutic actions against two different receptor subtypes (α1a and α1d) into a single compound. The dual-selective antagonists of Formula (I) simultaneously block both α1a and α1d receptors, combining the benefits of selective antagonism (reduced cardiovascular side effects) with comprehensive symptom coverage (both obstructive and irritative LUTS).
3Reliability
If current α1-AR antagonists are used, then BPH symptoms are treated, but concurrent use with PDE inhibitors is contraindicated due to increased cardiovascular risk
Solution Approach 1:
The patent converts the potential harm of cardiovascular interactions into a benefit by designing antagonists with such high selectivity for α1a/α1d over α1b receptors that the harmful interaction with PDE inhibitors is eliminated. The selective compounds maintain BPH treatment effectiveness while removing the contraindication, allowing beneficial combination therapy for patients with both LUTS and erectile dysfunction.
Data Source
AI summary
The present invention relates to substituted [4-(4-phenyl-piperazin-1-yl)-cyclohexyl]-urea compounds of Formula (I)and pharmaceutically acceptable forms thereof, as α1a/α1d adrenoreceptor modulators for the treatment of benign prostatic hypertrophy and lower urinary tract symptoms. The present invention also relates to pharmaceutical compositions comprising said new compounds, new processes to prepare these new compounds and new uses as a medicine as well as methods of treatment.