ABSTRACT
The application of physiologically based pharmacokinetic (PBPK) modeling has developed rapidly within the pharmaceutical industry and is becoming an integral part of drug discovery and development. In this study, we provide a cross pharmaceutical industry position on "how PBPK modeling can be applied in industry" focusing on the strategies for application of PBPK at different stages, an associated perspective on the confidence and challenges, as well as guidance on interacting with regulatory agencies and internal best practices.
Subject(s)
Drug Discovery/methods , Drug Industry/methods , Models, Biological , Pharmacokinetics , Drug Approval , HumansABSTRACT
PNQX (1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido[3, 4-f]quinoxaline-2,3-dione) is a potent AMPA (IC50 = 0.063 microM) and GlyN (IC50 = 0.37 microM) receptor antagonist that was developed in our laboratories. While possessing a desirable in vitro and in vivo activity profile, this compound suffers from low aqueous solubility. In an effort to improve its potency and physical properties, we have designed and synthesized novel ring-opened analogues 4, 6, 9, and 11. Modeling analyses demonstrated that, while the 5-substituent in these analogues was forced to adopt an out-of-plane conformation due to steric contacts with neighboring substituents, the overall structure retained a good fit to a previously described AMPA pharmacophore model. This nonplanar orientation may lessen efficient packing in the solid state, compared to PNQX, leading to increased water solubility. Indeed, several nonplanar analogues containing appropriate functionalities, for example, the sarcosine analogue 9, were found to retain AMPA (IC50 = 0.14 microM) and GlyN (IC50 = 0.47 microM) receptor affinity and possess improved aqueous solubility compared to PNQX. The synthesis and the SAR of these compounds are discussed.
Subject(s)
Excitatory Amino Acid Antagonists/chemical synthesis , Glycine/analogs & derivatives , Quinoxalines/chemical synthesis , Receptors, AMPA/antagonists & inhibitors , Receptors, Glycine/antagonists & inhibitors , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Anticonvulsants/metabolism , Anticonvulsants/pharmacology , Binding, Competitive , Cerebral Cortex/metabolism , Drug Design , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/metabolism , Excitatory Amino Acid Antagonists/pharmacology , Glycine/chemical synthesis , Glycine/chemistry , Glycine/metabolism , Glycine/pharmacology , In Vitro Techniques , Male , Mice , Models, Molecular , Quinoxalines/chemistry , Quinoxalines/metabolism , Quinoxalines/pharmacology , Rats , Receptors, AMPA/metabolism , Receptors, Glycine/metabolism , Solubility , Synaptosomes/metabolismABSTRACT
A semi-automated method to determine pKa values spectrophotometrically is described. The method uses the capabilities of a HPLC equipped with a diode array detector (DAD) as a flow injection apparatus. The advantages are low sample consumption, rapid sample throughput, high sensitivity, and precision. Experimental pKa values obtained for two model compounds, benzoic acid (approximately 4.0) and 2-aminopyridine (approximately 6.8), are consistent with literature values. Constant ionic strength was maintained for a wide pH range. Solubilized samples in non-aqueous solvents were also investigated. The weakening in pKa values, often seen when using non-aqueous solvents, was small (0.04-0.40 pH units) compared to conventional methods.
