Case Studies of CNS Drug Optimization—Medicinal Chemistry and CNS Biology Perspectives
Kevin J. Hodgetts · 2015
Brain penetration is expressed in terms of unbound drug levels in brain, plasma, and cerebrospinal fluid (CSF), and free brain concentration/free plasma concentration is used to more accurately predict and rationalize CNS target engagement and in vivo effects than B/P ratio. This chapter presents case studies illustrating the medicinal chemistry optimization of lead molecules to improve brain permeability and penetration. It considers how the structural modifications affect physicochemical properties during the optimization of brain penetration. The case studies are divided into two categories: optimization of passive permeability; and strategies for the mitigation of P-glycoprotein (P-gp) efflux. The medicinal chemistry tactics of conformational constraint; bioisosteric replacement; incorporation of fluorine; and increasing metabolic stability are used to optimize structural properties and passive permeability and to improve brain penetration.