Exposure brain

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio 10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Compound T-type FLIPR IP (nM) hERG IC50 (nM) L-type IC50 (nM) CL 

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The strategic placement of an 18F or 19F atom has also enabled positron emission tomography (PET) [7,8] and magnetic resonance imaging (MRI) [9,10] approaches to determine receptor occupancy and perform biodistribution studies, respectively. PET has also been used to study receptor expression patterns and aid in determining efficacious brain exposures and ultimately human efficacious doses. This topic will not be covered here, as it is covered in an earlier chapter in this volume. 

The incorporation of fluorine into a molecule has been widely used to alter the pharmacokinetic properties and overall drug-like properties of compounds. This includes affecting the metabolism, oral absorption, and brain penetration of these molecules [18]. Metabolism can be affected by addition of fluorine directly at or adjacent to the site of metabolism. In addition, substitution with fluorine can increase the lipophilicity of compounds which has been shown to dramatically affect both oral absorption and brain penetration. Finally, the electron-withdrawing characteristic of fluorine has been exploited to lower the P-gp liability of compounds and modulate the pKa of adjacent groups which resulted in increased brain exposure. In the following section, representative examples will highlight the powerful nature of fluorine to modulate overall drug-like properties. 

Incorporation of fluorine at a site adjacent to a "metabolic soft spot" has also been used as a strategy to increase duration of action. Linopir-dine (24) was among the first clinical compounds that enhanced potassium-evoked release of acetylcholine in preclinical models of AD [22]. Linopirdine showed no clinical efficacy and its human pharmacokinetic profile was suggested as the reason for this lack of clinical efficacy. Specifically noted was the molecule s poor brain exposure and short half-life due to formation of the N-oxides 25 and 26 (Table 3) [23,24]. Optimization of 24 resulted in replacement of the indolone core by the anthracenone 27, which had improved in vitro activity, but still exhibited a short duration of action. To improve the metabolic stability, fluorine... 

Structure-activity relations within chemical series have helped establish whether specific scaffolds and substitutions are an integral part of the Kvl.5 pharmacophore, or simply help display it. Frequently, property changes unrelated to Kvl.5 activity, such as unacceptable pharmacokinetic profiles, have prevented a thorough understanding of a particular pharmacophore. Other times, detailed pharmacophore characterization is compromised by a need to preserve or improve desirable properties in addition to Kvl.5 activity, such as oral bioavailability [43] or P-glycoprotein susceptibility, a predictor of reduced brain exposure [50]. 

Maternal hair predicts fetal brain exposure. Neurotoxicology 16 (4) 705-10. 

Additional selectivity profihng and pharmacokinetics of the maleimides are ideally required to assess their attractiveness and importance as in vivo tools. Nevertheless, exciting cellular inhibition of tau, in conjunction with varied degrees of brain exposure, suggests that these compounds could prove to be extremely interesting tools. 

Cemichiari, E., R. Brewer, G.J. Myers, D.O. Marsh, L.W. Lapham, C. Cox, C.F. Shamlaye, M. Berlin, P.W. Davidson, and T.W. Clarkson. 1995. Monitoring methylmercury during pregnancy Maternal hair predicts fetal brain exposure. Neurotoxicology 16(4) 705-710. 

Hitchcock SA, Pennington LD (2006) Structure-brain exposure relationships. J Med Chem 49(26) 7559-7583... 

In rats, i.v. administration of benzylpenicil-lin-CDS with an ethylene 1,2-diol spacer gave an AUC-based brain-exposure enhancement factor for benzylpenicillin of around 11 (Table... 

Raub, T.J. (2004) Early preclinical evaluation in support of hit identification and lead optimization for brain exposure. AAPS Workshop Optimization of Drug-Like Properties During Lead Optimization,... 

Structure-brain exposure relationships. Journal of Medicinal Chemistry, 49, 7559. 

Zhao R, Kalvass JC, Yanni SB, Bridges AS, and Pollack GM (2009) Fexofenadine brain exposure and the influence of blood-brain barrier P-glycoprotein after fexofenadine and terfenadine administration. Drug Metab Dispos 37 529-535. 

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