CNS drug development presents a fundamental constraint. Compounds must cross the blood-brain barrier while maintaining pharmacological activity at their target. This creates significant attrition in CNS programs. Many late-stage failures stem from issues that emerge earlier than expected, such as inadequate brain exposure at feasible doses or compounds that require
The blood-brain barrier receives considerable attention in CNS drug discovery, typically framed around tight junctions and physical integrity. In practice, however, compound performance often reflects a different constraint: active efflux. Proteins such as P-glycoprotein (MDR1/ABCB1) and BCRP (ABCG2) actively pump certain molecules back across the endothelium, limiting net brain exposure
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