Centrally Active Ghrelin Agonist for Blood-Brain Barrier Uptake
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Solution Overview
Problem
Existing small molecule ghrelin agonists face challenges in penetrating the blood-brain barrier, leading to unsatisfactory safety profiles and poor uptake in the central nervous system, limiting their clinical utility for centrally mediated diseases, and they struggle to maintain a balance of drug concentration across both central and peripheral compartments.
Innovation Solution
The compound 3-(1-(2,3-dichloro-4-methoxyphenyl) ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt acts as a ghrelin agonist with high blood-brain barrier permeability, achieving significant non-metabolized form distribution and establishing pharmacologically active concentrations in the brain, while minimizing brain accumulation, thus offering therapeutic effects at both central and peripheral levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule ghrelin agonists are administered to achieve therapeutic effects, then pharmacological activity is achieved, but blood-brain barrier penetration is insufficient leading to poor CNS uptake
Solution Approach 1:
The patent modifies molecular parameters of ghrelin agonists by introducing specific structural features (lipophilic groups, basic nitrogen atoms, cyclic structures) to enhance blood-brain barrier penetration while maintaining pharmacological activity. This resolves the contradiction by changing chemical parameters to improve CNS uptake without sacrificing therapeutic efficacy.
Solution Approach 2:
The invention creates composite molecular structures combining hydrophilic and lipophilic regions, creating amphipathic molecules that can interact with both aqueous environments and lipid membranes. This composite approach enables simultaneous solubility and membrane penetration, resolving the blood-brain barrier penetration issue while maintaining therapeutic effects.
2Reliability
If ghrelin agonists are administered to achieve centrally mediated disease treatment, then therapeutic effects are achieved, but safety profile deteriorates due to accumulation and toxicity
Solution Approach 1:
The patent designs molecules with optimized affinity and selectivity for the ghrelin receptor, achieving sufficient therapeutic effect without excessive accumulation in the brain. This partial action approach provides adequate CNS penetration for therapeutic efficacy while limiting over-accumulation that would cause toxicity, thus improving the safety profile.
Solution Approach 2:
The invention uses specific molecular structures as intermediaries that facilitate controlled transport across the blood-brain barrier. These structures act as mediators that enable sufficient drug entry for therapeutic effect while preventing uncontrolled accumulation, thereby resolving the safety profile issue.
3Reliability
If ghrelin agonists are administered to achieve CNS uptake, then central therapeutic effects are achieved, but balance of drug concentration across central and peripheral compartments deteriorates
Solution Approach 1:
The patent creates molecules with differentiated regional properties - lipophilic regions for membrane penetration and hydrophilic regions for solubility and peripheral distribution. This local quality differentiation enables selective CNS uptake while maintaining appropriate peripheral compartment concentrations, resolving the concentration balance issue.
Solution Approach 2:
The invention designs molecules with dynamic distribution characteristics that allow preferential CNS penetration while maintaining reversible equilibrium with peripheral compartments. The molecular structure enables dynamic adjustment of drug distribution, achieving adequate CNS uptake while preserving overall concentration balance across compartments.
Data Source
AI summary
The new compound 3-(1-(2,3-dichloro-4-methoxyphenyl) ethyl)-1-methyl-l-(l,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt has a high capability to permeate through the blood-brain barrier and to display, at central nervous system level, a consistent ghrelin agonist activity; the compound is effective in the treatment and/or prevention of a medical condition mediated by the ghrelin receptor in the central nervous system. In particular, in experimental tests, the compound has shown high efficacy in the treatment of neurotoxic damage, with a useful combined pattern of neuroprotective effects both at central and peripheral level. The compound is further useful in the treatment of conditions which require a reduction of the heart rate. The compound is pharmacologically active at low to moderate doses, thus showing a favourable therapeutic index.