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Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity
TLDR
Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel, indicating potential for an excellent clinical safety profile.
Prediction of Human Pharmacokinetics From Preclinical Information: Comparative Accuracy of Quantitative Prediction Approaches
TLDR
Use of predictive methods involving either single‐species in vivo data or in vitro human liver microsomes can quantitatively predict human in vivo pharmacokinetics are suggested and the possibility of streamlining the predictive methodology through use of a single species or use only of human in vitro microsomal preparations is suggested.
PEGylated Proteins: Evaluation of Their Safety in the Absence of Definitive Metabolism Studies
TLDR
Assuming that toxicological evaluation of a biological molecule of interest is complete and satisfactory therapeutic windows are achieved, the data contained in this review indicate that the PEG associated with a protein or other biological molecule does not represent an additional unquantified risk to humans.
Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: challenges to the discovery scientist.
TLDR
This paper will review the literature around marketed prodrugs and determine the most appropriate prodrug characteristics, examine potential Discovery approaches to optimising prodrug delivery and recommend a strategy for prosecuting an oral prodrug approach.
Towards a drug concentration effect relationship for QT prolongation and torsades de pointes.
TLDR
Concentration/effect relationships are apparent such that compounds with positive results in preclinical assays may prove safe, provided that the maximum concentrations expected in the patient population are significantly lower than those required to prolong QT.
PEG and PEG conjugates toxicity: towards an understanding of the toxicity of PEG and its relevance to PEGylated biologicals
TLDR
The doses used clinically for current and many future PEGylated biologicals are low and will result in exposures to PEG significantly lower than that required to elicit PEG toxicity.
A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder.
TLDR
This study provides a parallel investigation of CNS penetration of antimuscarinic OAB agents in vivo and assessment of physical properties and permeability in cell monolayers in vitro and adds further understanding of the roles of passive transcellular permeability and P-gp in determining CNS penetration.
The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF‐4878691)
TLDR
These doses of TLR7 stimulation results in a pharmacologic response at levels commensurate with predicted antiviral efficacy, but these doses are associated with SAEs, raising concerns about the therapeutic window of this class of compounds for the treatment of HCV infection.
Potent and selective nonpeptidic inhibitors of procollagen C-proteinase.
TLDR
Sulfonamide 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold).
Pre-clinical pharmacokinetics of UK-453,061, a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), and use of in silico physiologically based prediction tools to predict the oral
TLDR
This study demonstrates the utility of using in silico PBPK approaches to make predictions of human pharmacokinetics before dosing for the first time in humans.
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