From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Computational Chemistry

Background:

• Initial screening identified Compound 1 with micromolar activity at the mu opiate receptor.
• Optimization efforts were initiated to enhance the potency and develop novel mu opiate receptor ligands.

Purpose of the Study:

• To design and synthesize analogues of Compound 1 with improved affinity for the mu opiate receptor.
• To compare the utility of pharmacophoric pattern matching and topological similarity for analogue design.
• To establish structure-activity relationships (SAR) guiding further optimization.

Main Methods:

• Utilized computer-aided pharmacophoric pattern comparison for analogue design.
• Employed topological similarity assessments to guide the development of new compounds.
• Synthesized novel chemical entities based on SAR derived from both similarity approaches.

Main Results:

• Compound 40, a novel N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl)acetamide derivative, was synthesized.
• Compound 40 demonstrated a subnanomolar affinity for the mu (human) opiate receptor, with an IC(50) of 0.9 nM.
• The study identified SAR insights applicable to the N-3 position of the spirocycle moiety for future analogue design.

Conclusions:

• The combined application of pharmacophoric and topological similarity concepts effectively guided the optimization process.
• Compound 40 represents a significant advancement, showcasing high affinity for the mu opiate receptor.
• This research provides a foundation for developing a new series of potent mu opiate receptor modulators.