Design and Identification of a Novel, Functionally Subtype Selective GABA_A Positive Allosteric Modulator...

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• GABA-A receptors are crucial targets for neurological disorders.
• Developing subtype-selective modulators presents significant challenges.
• Positive allosteric modulators (PAMs) offer a nuanced therapeutic approach.

Purpose of the Study:

• To design, optimize, and evaluate novel imidazopyridazine-based PAMs for GABA-A receptor subtypes.
• To achieve high functional selectivity for specific GABA-A receptor subtypes.
• To identify preclinical and clinical candidates for further development.

Main Methods:

• Iterative design and synthesis of imidazopyridazine compounds.
• Evaluation of binding affinity and functional activity at GABA-A receptor subtypes.
• Application of a probability-based assessment to prioritize development efforts.
• Preclinical safety studies and candidate selection.

Main Results:

• Multiple subseries of compounds were explored based on initial hits.
• Functional selectivity proved challenging to achieve across all subseries.
• A probability-based approach successfully focused efforts on a promising subseries.
• Two precandidates were identified and advanced to preclinical safety studies.
• The clinical candidate PF-06372865 was ultimately identified.

Conclusions:

• Novel imidazopyridazine-based PAMs targeting GABA-A receptors were successfully developed.
• A strategic, probability-based approach was effective in overcoming design challenges.
• The identified clinical candidate, PF-06372865, demonstrates the success of this optimization strategy.