Harnessing Preclinical Data as a Predictive Tool for Human Brain Tissue Targeting.
ACS Chem Neurosci
; 12(6): 1007-1017, 2021 03 17.
Article
in En
| MEDLINE
| ID: mdl-33651587
ABSTRACT
One of the objectives within the medicinal chemistry discipline is to design tissue targeting molecules. The objective of tissue specificity can be either to gain drug access to the compartment of interest (e.g., the CNS) for Neuroscience targets or to restrict drug access to the CNS for all other therapeutic areas. Both neuroscience and non-neuroscience therapeutic areas have struggled to quantitatively estimate brain penetration or the lack thereof with compounds that are substrates of efflux transport proteins such as P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) that are key components of the blood-brain barrier (BBB). It has been well established that drug candidates with high efflux ratios (ER) of these transporters have poor penetration into brain tissue. In the current work, we outline a parallel analysis to previously published models for the prediction of brain penetration that utilize an alternate MDR1-MDCK cell line as a better predictor of brain penetration and whether a correlation between in vitro, rodent data, non-human primate (NHP), and human in vivo brain penetration data could be established. Analysis of structural and physicochemical properties in conjunction with in vitro parameters and preclinical in vivo data has been highlighted in this manuscript as a continuation of the previously published work.
Key words
Blood−brain barrier (BBB); Madin−Darby canine kidney (MDCK); National Institutes of Health (NIH); Netherlands Cancer Institute (NKI); P-glycoprotein (P-gp); brain availability; breast cancer resistant protein (BCRP); central nervous system (CNS); cerebrospinal fluid (CSF); drug concentration; efflux ratio (ER); human CNS exposure; in vitro assays; in vitro to in vivo correlation (IVIVC); multidrug resistance protein 1 (MDR1); passive permeability; transporters; unbound fraction
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain
/
Neoplasm Proteins
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
ACS Chem Neurosci
Year:
2021
Document type:
Article
Affiliation country: