Peter McNamara, Ph.D.
Director of Pharmacology
John J. Isbell, Ph.D.
Director of Analytical Sciences and DMPK
The GNF Pharmacology Department is highly integrated with the other drug discovery departments, and our scientists collaborate along the entire spectrum of drug discovery efforts. We supply input and key information to the project teams to help them optimize the efficacy of drug candidates while reducing the potential liabilities of the compounds. This includes providing in vitro and in vivo assessment of the drug metabolism, pharmacokinetic, efficacy, and safety profiles of novel compounds synthesized by GNF’s medicinal chemists.
The Pharmacology Department consists of the DMPK (Drug Metabolism and Pharmacokinetics) group, which is focused on developing and running ADMET (absorption, distribution, metabolism, excretion, and toxicology) assays, and an in vivo model group focused on establishing and running pre-clinical models of human disease.
DMPK Group Capabilities
One common reason many early drug candidates fail before reaching the market is inappropriate ADMET properties. Thus, having predictive ADMET profiles of drug candidates during preclinical development should provide a major advantage in achieving clinical success.
The goal of our DMPK group is to develop high throughput testing methods and provide rapid and robust information necessary for critical ‘go or no-go’ decision making. Implementing in vitro ADMET studies early in the drug discovery process requires increased throughput. This poses three challenges: i) complex, assay-dependent automation and assay development; ii) multiple assay platforms; and iii) significant reagent and compound costs. The GNF DMPK group has introduced efficient methods to help identify the optimal molecules from thousands of medicinal chemistry compounds synthesized for drug discovery projects. Parallel assessments of in vivo pharmacokinetics, in vitro ADME characterization, and pharmacological properties are carried out at a very early stage in drug discovery projects, and our group utilizes state-of-the-art technology such as advanced automation (higher density plate format and robotics) along with LC-MS/MS with automated method development.
We are able to characterize numerous in vitro parameters such as metabolic stability, CYP (cytochrome p450) inhibition and induction, drug/drug interactions, metabolite identification, permeability, transport and efflux [via PAMPA (Parallel Artificial Membrane Permeation Assay) and Caco-2 assays], cytotoxicity, gene toxicity (e.g., Ames), hERG testing and broad receptor/transporter cross-reactivity. In vivo PK and tissue distribution studies are conducted with excellent throughput, generating in vivo ADME information for hundreds of compounds per year. The data gleaned from these experiments aids in the understanding of the pharmacokinetic-chemical structure activity relationship, increasing the quality of GNF drug candidates.
Models of Human Disease
The Pharmacology Department has a core group of scientists dedicated to developing and running preclinical models of human disease in metabolic/cardiovascular disease, oncology, and immunology. The primary focus for this group is to determine the efficacy of drug candidates in preclinical models of human disease. This group also strives to establish pharmacodynamic (PD) markers to assist in providing a PK/PD efficacy measurement.
The post-genomic era has brought forward numerous potential drug targets, and a major challenge is now validating each of these targets in the context of their relationship to human disease. At GNF, our pharmacologists are using classical pharmacological transgenic and knockout technologies (including tissue-specific and conditional knockouts) to aid in target validation. In addition, novel ways of knocking in or knocking down genes of interest in vivo are being explored.
- A Modern in vivo PK Paradigm: Combining snapshot, rapid and full PK approaches to optimize and expedite early drug discovery. Chun Li, Bo Liu, Jonathan Chang, Todd Groessl, Matt Zimmerman, You-Qun He, John Isbell and Tove Tuntland. Drug Discovery Today, Vol. 18, 1-2, pp 71-78, Jan. 2013
- Bo Liu, Jonathan Chang, William P. Gordon, John Isbell, Yingyao Zhou and Tove Tuntland Snapshot PK: a rapid rodent in vivo preclinical screening approach. Drug Discovery Today 2008;13:7-8.
- Epple R, Azimioara M, Russo R, Xie Y, Wang X, Cow C, Wityak J, Karanewsky D, Bursulaya B, Kreusch A, et al. 3,4,5-Trisubstituted isoxazoles as novel PPARdelta agonists. Part 2. Bioorg Med Chem Lett 2006;16(21):5488-92.
- Tully DC, Liu H, Chatterjee AK, Alper PB, Williams JA, Roberts MJ, Mutnick D, Woodmansee DH, Hollenbeck T, Gordon P, et al. Arylaminoethyl carbamates as a novel series of potent and selective cathepsin S inhibitors. Bioorg Med Chem Lett 2006;16(19):5107-11.
- Jiang T, Kuhen KL, Wolff K, Yin H, Bieza K, Caldwell J, Bursulaya B, Tuntland T, Zhang K, Karanewsky D, et al. Design, synthesis, and biological evaluations of novel oxindoles as HIV-1 non-nucleoside reverse transcriptase inhibitors. Part 2. Bioorg Med Chem Lett 2006;16(8):2109-12.