Preclinical Pharmacology

New York City, NY, United States

Preclinical Pharmacology

New York City, NY, United States
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Treiber A.,Hegenheimermattweg | De Kanter R.,Hegenheimermattweg | Roch C.,Preclinical Pharmacology | Von Raumer M.,Idorsia Pharmaceuticals Ltd | And 4 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2017

The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX1 andOX2) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-Ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met. © 2017 by The American Society for Pharmacology and Experimental Therapeutics.


Zhong Z.,Imclone Systems | Carroll K.D.,Imclone Systems | Policarpio D.,Imclone Systems | Osborn C.,Imclone Systems | And 18 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Transforming growth factor β (TGFβ) is a pleiotropic cytokine that affects tumor growth, metastasis, stroma, and immune response. We investigated the therapeutic efficacy of anti-TGFβ receptor II (TGFβ RII) antibody in controlling metastasis and tumor growth as well as enhancing antitumor immunity in preclinical tumor models. Experimental Design: We generated neutralizing antibodies to TGFβ RII and assessed the antibody effects on cancer, stroma, and immune cells in vitro. The efficacy and mechanism of action of the antibody as monotherapy and in combination with chemotherapy in suppression of primary tumor growth and metastasis were evaluated in several tumor models. Results: Anti-TGFβ RII antibody blocked TGFβ RII binding to TGFβ 1, 2, and 3, and attenuated the TGFβ-mediated activation of downstream Smad2 kinase, invasion of cancer cells, motility of endothelial and fibroblast cells, and induction of immunosuppressive cells. Treatment with the antibody significantly suppressed primary tumor growth and metastasis and enhanced natural killer and CTL activity in tumorbearing mice. Immunohistochemistry analysis showed cancer cell apoptosis and massive necrosis, and increased tumor-infiltrating T effector cells and decreased tumor-infiltrating Gr-1+ myeloid cells in the antibody-treated tumors. Fluorescence-activated cell sorting analysis indicated the significant reduction of peripheral Gr-1+/CD11b+ myeloid cells in treated animals. Concomitant treatment with the cytotoxic agent cyclophosphamide resulted in a significantly increased antitumor efficacy against primary tumor growth and metastasis. Conclusions: These preclinical data provide a foundation to support using anti-TGFβ RII antibody as a therapeutic agent for TGFβ RIIβdependent cancer with metastatic capacity. ©2010 AACR.


Jian Y.,Indiana University – Purdue University Indianapolis | Ames D.M.,Indiana University – Purdue University Indianapolis | Ouyang H.,Preclinical Pharmacology | Li L.,Indiana University – Purdue University Indianapolis | Li L.,Indiana University
Organic Letters | Year: 2015

Nucleoside/nucleotide/oligonucleotide photoreactions usually result in a number of products simultaneously due to a wide range of conformers existing at a given time. Such a complicated reaction pattern makes it difficult for one to focus on a single DNA photoproduct and elucidate the requirements for its formation. A rare example of thymidine photoreaction in microcrystals is reported, where 5-thyminyl-5,6-dihydrothymine, e.g.; the spore photoproduct (SP), is produced as the dominant species in ∼85% yield. This unprecedented high yield clears the major obstacle for future SP photochemistry studies in detail. © 2015 American Chemical Society.


Lin G.,Indiana University – Purdue University Indianapolis | Jian Y.,Indiana University – Purdue University Indianapolis | Ouyang H.,Preclinical Pharmacology | Li L.,Indiana University – Purdue University Indianapolis | Li L.,Indiana University
Organic Letters | Year: 2014

Pyrimidine (6-4) pyrimidone photoproduct (6-4PP), a common DNA photolesion formed under solar irradiation, was indicated to hydrolyze under strong basic conditions, breaking the N3-C4 bond at the 5′-thymine. The reanalysis of this reaction revealed that the resulting water adduct may not be stable as previously proposed; it readily undergoes an esterification reaction induced by the 5-OH group at 6-4PP to form a five-membered ring, eliminating a molecule of ammonia. © 2014 American Chemical Society.


PubMed | Preclinical Pharmacology
Type: Journal Article | Journal: Amino acids | Year: 2013

Understanding the physicochemical and structural properties of peptides are important prerequisites for the rational design of bioactive peptides and peptidomimetics. The present contribution reviews methods used for the assessment and prediction of lipophilicity (or hydrophobicity) and their correlation with structural elements of peptides and closely related peptidomimetics.

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