Angela C Doran

Pfizer Inc., New York City, NY, United States

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Publications (6)21.9 Total impact

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    ABSTRACT: In rats, oxycodone, diphenhydramine, and [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine (CE-157119) undergo net active influx at the blood–brain barrier (BBB) based on significantly greater interstitial fluid compound concentrations (CISF) than unbound plasma compound concentrations (Cp,u). Oxycodone and diphenhydramine have CISF:Cp,u of 3.0 and 5.5, respectively, while CE-157119 has an unbound brain compound concentration (Cb,u):Cp,u of 3.90; Cb,u is a high-confidence CISF surrogate. However, only CE-157119 has published dog and nonhuman primate (nhp) neuropharmacokinetics, which show similar Cb,u:Cp,u (4.61 and 2.04, respectively) as rats. Thus, diphenhydramine underwent identical interspecies neuropharmacokinetics studies to determine if its net active BBB influx in rats replicated in dogs and/or nhp. The single-dose-derived rat Cb,u:Cp,u (3.90) was consistent with prior steady-state-derived CISF:Cp,u and similar to those in dogs (4.88) and nhp (4.51–5.00). All large animal interneurocompartmental ratios were ≤1.8-fold different than their rat values, implying that diphenhydramine has constant and substantial Cb,u-favoring disequilibria in these mammals. Accordingly, the applied Cb,u-forecasting methodology accurately predicted [estimated mean (95% confidence interval) of 0.84 (0.68, 1.05)] Cb,u from each measured Cp,u in large animals. The collective datasets suggest these Cb,u-preferring asymmetries are mediated by a species-independent BBB active uptake system whose identification, full characterization, and structure–activity relationships should be prioritized for potential exploitation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
    Journal of Pharmaceutical Sciences 03/2014; · 3.13 Impact Factor
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    ABSTRACT: Previous publications suggest that interstitial fluid compound concentrations (C(ISF)) best determine quantitative neurotherapeutic pharmacology relationships, although confirming large animal C(ISF) remains elusive. Therefore, this work primarily evaluated using respective acute dose, rat-derived unbound brain compound concentration-to-unbound plasma compound concentration ratios (C(b,u)/C(p,u)) to project accurately dog and nonhuman primate (nhp) C(b,u), a C(ISF) surrogate, from measured C(p,u) for the highly permeable non-P-glycoprotein substrates N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) and [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine (CE-157119) and the P-glycoprotein substrates risperidone and 9-hydroxyrisperidone. First, in rats, it was determined for eight of nine commercial compounds that their single-dose-derived C(b,u)/C(p,u) were ≤2.5-fold different from their steady-state values; for all nine drugs, their C(b,u)/C(p,u) were ≤2.5-fold different from their steady-state C(ISF)/C(p,u) (Drug Metab Dispos 37:787-793, 2009). Subsequently, PF-4778574, CE-157119 and risperidone underwent rat, dog, and nhp neuropharmacokinetics studies. In large animals at each measured C(p,u), the methodology adequately predicted [estimated mean (95% confidence interval) of 1.02 (0.80, 1.29)] the observed C(b,u) for PF-4778574 and CE-157119 but underpredicted [0.17 (0.12, 0.22)] C(b,u) for risperidone and 9-hydroxyrisperidone. The data imply that forecasting higher species C(b,u) from a measured C(p,u) and rat acute dose-determined C(b,u):C(p,u) is of high confidence for nonefflux transporter substrates that show net passive diffusion (PF-4778574) or net active influx (CE-157119) at the blood-brain barrier in rats. However, this methodology appears ineffective for correctly predicting large animal C(b,u) for P-glycoprotein substrates (risperidone and 9-hydroxyrisperidone) because of their apparently much greater C(p,u)-favoring C(b,u):C(p,u) asymmetry in rats versus dogs or nhp. Instead, for such P-glycoprotein substrates, large animal-specific cerebrospinal fluid compound concentrations (C(CSF)) seemingly best represent C(b,u).
    Drug metabolism and disposition: the biological fate of chemicals 08/2012; 40(11):2162-73. · 3.74 Impact Factor
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    ABSTRACT: Selective activation of the Group II metabotropic glutamate receptors 2/3 (mGlu2/3) by either full agonists or positive allosteric modulators (PAMs) show anxiolytic activity. In the present study the anxiolytic profile of mGlu2/3 receptor agonists LY-354740 and LY-404039 and the mGlu2 receptor PAM 1-methyl-2-((cis-3-methyl-4-(4-trifluoromethyl-2-methoxy)-phenyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyridine (MTFIP) were evaluated using neurophysiology-based assays. Activation of mGlu2/3 receptors by these compounds, as well as the positive control diazepam, significantly decreased the frequency of hippocampal theta oscillation elicited by stimulation of the brainstem nucleus pontis oralis (nPO), a characteristic action of anxiolytic compounds. Since the nPO is a critical region involved in regulation of rapid eye movement sleep, mGlu2/3 receptor activators were also tested on sleep parameters, as well as on cortical and hippocampal encephalography (EEG) activity. Both mGlu2/3 agonists and the mGlu2 PAM significantly prolonged REM sleep latency and reduced total REM sleep duration while during the active awake state all compounds lowered hippocampal peak theta frequency. However, diazepam and mGlu2/3 agonists/PAM elicited opposite changes in cortical EEG delta and beta bands. Delta power significantly increased after any of the mGlu2/3 compounds but decreased after diazepam. In the beta band, mGlu2/3 receptor agonists dose-dependently decreased beta power in contrast to the well-known beta activation by diazepam. These effects lasted 3-4h and could not be explained by modest, transient changes (<1h) in waking and slow wave sleep. The current observations support the role of mGlu2/3 receptor activators as potential anxiolytic compounds, but indicate a distinct action on cortical EEG activity which is different from the effects of GABA(A) PAMs. This article is part of a Special Issue entitled 'Anxiety and Depression'.
    Neuropharmacology 07/2011; 62(1):226-36. · 4.11 Impact Factor
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    ABSTRACT: A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.
    Journal of Medicinal Chemistry 03/2011; 54(6):1724-39. · 5.61 Impact Factor
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    ABSTRACT: The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.
    Bioorganic & medicinal chemistry letters 04/2009; 19(9):2524-9. · 2.65 Impact Factor
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    ABSTRACT: The synthesis and structure-activity relationship (SAR) of a novel series of 3-(imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers, derived from a high throughput screening (HTS), are described. Subsequent optimization led to identification of potent, metabolically stable and orally available mGluR2 positive allosteric modulators (PAMs).
    Bioorganic & medicinal chemistry letters 10/2008; 18(20):5493-6. · 2.65 Impact Factor