The blood-brain barrier (BBB) is a critical factor in the success of central nervous system (CNS) drugs, as it determines their ability to reach the brain and exert therapeutic effects. Successful CNS drugs typically have smaller molecular weights, lipophilicity, and hydrogen bond donor/acceptor counts compared to general therapeutics. Pharmacokinetic properties, such as solubility, permeability, and metabolic stability, can be manipulated by medicinal chemists to optimize drug performance. The BBB is primarily permeable to small, lipophilic molecules that passively diffuse through it, while larger or more polar molecules may require active transport. However, active transport and efflux mechanisms also play a role in CNS drug penetration. Key physicochemical properties that influence BBB penetration include lipophilicity (LogP), molecular weight, polar surface area (PSA), and hydrogen bonding capacity. LogP is a critical factor, with optimal values for CNS drugs typically ranging from 1.5 to 2.7. PSA is also important, with values below 90 Ų generally associated with successful BBB penetration. Hydrogen bonding capacity, measured by the number of nitrogen and oxygen atoms (N+O), is another key factor, with a sum of five or less indicating a high probability of CNS penetration. Molecular flexibility and rotatable bonds also influence BBB penetration, with excessive flexibility potentially hindering drug passage through the BBB. Pharmacokinetic properties such as metabolic stability, protein binding, and hERG inhibition are also crucial for CNS drug success. Metabolic stability is important for maintaining drug levels in the body, while protein binding can affect drug distribution and efficacy. hERG inhibition is a concern for drugs that may cause life-threatening arrhythmias. The "Rule of Five" is a widely used guideline for CNS drug development, suggesting that compounds with molecular weights ≤500, LogP ≤5, ≤5 hydrogen bond donors, and ≤10 hydrogen bond acceptors are more likely to penetrate the BBB. Computational approaches, such as QSAR models and molecular descriptors, are used to predict BBB penetration and optimize drug design. These methods consider factors such as PSA, LogP, and molecular flexibility to identify compounds with favorable physicochemical properties for CNS drug development. Comparative studies have shown that CNS drugs generally have smaller molecular weights, lower PSA, and lower LogP values compared to non-CNS drugs. These findings highlight the importance of balancing physicochemical properties to achieve successful CNS drug development.The blood-brain barrier (BBB) is a critical factor in the success of central nervous system (CNS) drugs, as it determines their ability to reach the brain and exert therapeutic effects. Successful CNS drugs typically have smaller molecular weights, lipophilicity, and hydrogen bond donor/acceptor counts compared to general therapeutics. Pharmacokinetic properties, such as solubility, permeability, and metabolic stability, can be manipulated by medicinal chemists to optimize drug performance. The BBB is primarily permeable to small, lipophilic molecules that passively diffuse through it, while larger or more polar molecules may require active transport. However, active transport and efflux mechanisms also play a role in CNS drug penetration. Key physicochemical properties that influence BBB penetration include lipophilicity (LogP), molecular weight, polar surface area (PSA), and hydrogen bonding capacity. LogP is a critical factor, with optimal values for CNS drugs typically ranging from 1.5 to 2.7. PSA is also important, with values below 90 Ų generally associated with successful BBB penetration. Hydrogen bonding capacity, measured by the number of nitrogen and oxygen atoms (N+O), is another key factor, with a sum of five or less indicating a high probability of CNS penetration. Molecular flexibility and rotatable bonds also influence BBB penetration, with excessive flexibility potentially hindering drug passage through the BBB. Pharmacokinetic properties such as metabolic stability, protein binding, and hERG inhibition are also crucial for CNS drug success. Metabolic stability is important for maintaining drug levels in the body, while protein binding can affect drug distribution and efficacy. hERG inhibition is a concern for drugs that may cause life-threatening arrhythmias. The "Rule of Five" is a widely used guideline for CNS drug development, suggesting that compounds with molecular weights ≤500, LogP ≤5, ≤5 hydrogen bond donors, and ≤10 hydrogen bond acceptors are more likely to penetrate the BBB. Computational approaches, such as QSAR models and molecular descriptors, are used to predict BBB penetration and optimize drug design. These methods consider factors such as PSA, LogP, and molecular flexibility to identify compounds with favorable physicochemical properties for CNS drug development. Comparative studies have shown that CNS drugs generally have smaller molecular weights, lower PSA, and lower LogP values compared to non-CNS drugs. These findings highlight the importance of balancing physicochemical properties to achieve successful CNS drug development.