Physicochemical properties underline all aspects of drug action and profoundly impact the success rate of drug candidates in the clinic. Property based drug design is, therefore, a critical paradigm in hit and lead optimization towards drug-like molecules
with optimal pharmacodynamics, pharmacokinetic and safety profiles. The sixth annual Property-Based Drug Design features the latest developments and case studies in small molecule research in cancer, autoimmune and CNS
drug discovery, including hot biologics, macrocycles, immuno-oncology and epigenetics. It will also showcase technologies and strategies for prediction and evaluation of biophysical and physicochemical properties for molecules.
This symposium follows the popular fourteenth annual Mastering Medicinal Chemistry Conferences (June 13-15, 2017), and together these events will provide four full days of programming on the hottest trends and targets being pursued
in medicinal chemistry. We invite you to present a poster, or to attend to learn from and network with the leading experts from around the globe.
Who should attend: Vice Presidents, Directors and Senior Scientists in the pharmaceutical industry and academia working in Medicinal Chemistry, Small Molecule Drug Discovery and Research Technologies, Pharmacokinetics (DMPK), Early Pharmaceutics,
Computational Chemistry, Analytical Sciences, and Physical Chemistry
Final Agenda
Thursday, June 15
12:00 pm Registration
5:30 Chairperson’s Opening Remarks
Mark Smythe, Ph.D., Founder & VP, Protagonist Therapeutics
5:40 KEYNOTE PRESENTATION: Optimizing Properties of Cyclic Peptides and other Difficult Molecules
Scott Lokey, Ph.D., Professor, PBSci-Chemistry & Biochemistry Department, Physical & Biological
Sciences, University of California Santa Cruz
Macrocyclic peptides whose properties place them well outside the Rule of 5 can nonetheless exhibit drug-like behavior, including passive cell permeability and oral bioavailability. These exceptional molecules have stimulated efforts to understand the
structure-property relationships that underlie their outlier behavior. I will discuss our latest results from a series of studies using synthetic, biophysical, and analytical tools designed to probe the physicochemical constraints that govern ADME
behavior in macrocycles in the MW~1000 range.
6:10 KEYNOTE PRESENTATION: Oral Delivery of Constrained Peptides to Treat Inflammatory Bowel Disease
Mark Smythe, Ph.D., Founder & VP, Protagonist Therapeutics
Protagonist Therapeutics is a clinical-stage company with a proprietary technology focused on discovering and developing peptide-based drug candidates to address unmet medical needs. Our focus is on developing first-in-class oral peptide drugs that target
biological pathways of marketed injectable antibody drugs. This presentation will outline the strategies and molecular characteristics required to develop potent antagonists of undruggable targets that are stable to the gastrointestinal tract and
suitable for oral delivery.
6:40 End of Day
FRIDAY, June 16
8:30 am Chairperson’s Remarks
Martin Pettersson, Ph.D., Associate Research Fellow, Neuroscience & Pain Medicinal Chemistry, Pfizer, Inc.
8:40 Quantitative Assessment of the Impact of Fluorine Substitution on P Glycoprotein Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability
Martin Pettersson, Ph.D., Associate Research Fellow, Neuroscience & Pain Medicinal
Chemistry, Pfizer, Inc.
Strategic use of fluorine is an important tactic in lead optimization. However, replacing a hydrogen atom with a fluorine atom leads to a significant increase in molecular weight that is disproportionate to the corresponding increase in molecular volume.
This presentation will describe a pairwise analysis and statistical modeling of the impact of fluorine substitution on various ADME parameters such as P-gp mediated efflux, passive permeability, metabolic stability and lipophilicity.
9:10 Modeling In Vivo Drug Distribution and Efficiency using HPLC Based Membrane and Protein Binding Properties
Klara Valko, Ph.D., Director/Honorary professor, Bio-Mimetic Chromatography
Balancing between potency and chromatographically determined membrane and protein binding can help with the selection of drug discovery compounds that have a greater probability of having the desired in vivo ADME properties.
The standardization of chromatographic procedures enables collection of data for inter-laboratory comparison and direct applications in published models. This technology can predict compounds’ in vivo behavior
for the fraction of the cost of in vivo profiling.
9:40 Combining Measurements and Predictions to Accelerate PK Optimization
Bernard Faller, Ph.D., Director Discovery ADME, Novartis Institutes for BioMedical Research,
Basel, Switzerland
Discovery ADME assays have been implemented in the late nineties to reduce the attrition of development candidates caused by pharmacokinetic issues through identification of liabilities at a time the chemical structure could still be modified. Data accumulated
using true discovery quality molecules help us understand better what is the assay variability in a real discovery setup. Factoring in variability allows filtering out assay noise more effectively and helps building more meaningful prediction models.
This lecture will show what kind of assay resolution one can realistically achieve and what we are able to do/not do with current prediction models
10:10 Coffee Break
10:40 Predicting Clearance Active Rate Determining Step and DDI Using Extended Clearance Classification System: Industrial Perspective
Ayman El-Kattan, Ph.D., Associate Research Fellow, PDM, Pfizer, Inc.
Successful assessment of mechanism of action of a new chemical entity (NME) is in part determined by accurate prediction of clearance and potential DDI liabilities in human. Recently, the drug industry is realizing a major shift in the chemical space
that is associated with change in drug disposition, where metabolism is no longer the main rate determining step of NME clearance. Early identification of this step in drug discovery will enable more proactive clearance profiling screening that is
efficient and increase the likelihood of accurate clearance and DDI prediction and assessment of mechanism of action.
11:10 Building New Bridges between in vitro and in vivo in Early Drug Discovery: Where Molecular Modeling Meets Systems Biology
Robert Pearlstein, Ph.D., Senior Research Investigator I, Novartis Institutes for BioMedical
Research
We demonstrate the importance of drug design criteria based on target dynamics, drug PK, and binding kinetics versus the conventional use of static equilibrium drug-target occupancy criteria (e.g. IC50, Kd) that does not typically apply to the in vivo setting. We show that compounds can be designed on the basis of binding kinetics (as reflected in calculated target and drug solvation properties), which connects seamlessly with PK and target dynamics. Our work on herg blockade exemplifies the effect
of extreme target dynamics on binding.
11:40 Rational Bioavailability Design: Optimizing Bioavailability during Lead Optimization with Global Sensitivity Analysis of Physiologically-Based Pharmacokinetic Simulations
Pankaj R. Daga, Ph.D., Senior Scientist, Cheminformatics, Simulations-Plus, Inc.
Improving bioavailability of newly designed compounds during lead optimization is a challenging task; especially when over a dozen compound properties need to be adjusted. Since the difficulty of multi-parameter optimization grows exponentially with number
of variables, efficient %F optimization requires identifying the few most influential properties for specific chemical series. This presentation will discuss how we collectively applied ADME (ADMET Predictor) and PBPK (GastroPlus) models for three
different chemical series. The resulting analysis identified the important few properties to adjust for the series as a whole, as well as more specific advice for optimizing %F around particular compounds of interest.Improving bioavailability of newly
designed compounds during lead optimization is a challenging task; especially when over a dozen compound properties need to be adjusted. Since the difficulty of multi-parameter optimization grows exponentially with number of variables, efficient %F
optimization requires identifying the few most influential properties for specific chemical series. This presentation will discuss how we collectively applied ADME (ADMET Predictor) and PBPK (GastroPlus) models for three different chemical series.
The resulting analysis identified the important few properties to adjust for the series as a whole, as well as more specific advice for optimizing %F around particular compounds of interest.
12:10 pm Enjoy Lunch on Your Own
1:40 Chairperson’s Remarks
Kap-Sun Yeung, Ph.D., Principal Scientist , Discovery Chemistry, Bristol-Myers Squibb
1:50 Improved Prediction Model of Lipophilicity and its Integration with Other QSAR Models
Ignacio Aliagas, MSc., Scientist, Chemoinformatics, Discovery Chemistry, Genentech
An in-house QSAR model has been developed at Genentech to improve the LogD predictions from commercially available software. The model is trained using internally measured LogD. The LogD predictions are reduced significantly after applying the model correction.
Other QSAR benefit from the improved lipophilicity predictions and have been integrated with desktop tools to facilitate their calculation.
2:20 Discovery of an HCV NS5B Replicase Allosteric Inhibitor Advanced to Phase 1 Clinical Studies
Kap-Sun Yeung, Ph.D., Principal Scientist , Discovery Chemistry, Bristol-Myers Squibb
HCV NS5B replicase is an important target for identifying direct acting anti-HCV drugs. Starting from a simple template and a screening hit, an NS5B allosteric inhibitor clinical candidate was identified via a structure-based approach. The optimization
process to achieve a delicate balance of molecular properties for potency, ADMET profile, formulation, and the Phase I results that demonstrated the compound is safe and well-tolerated with human PK properties better than predicted, will be presented.
2:50 Using Physchem Measurements to Assess Tissue Distribution and Brain Free Fraction
Carol Moraff, Scientific Associate I, Novartis Institutes for BioMedical Research
Tissue distribution and brain free fraction measurements predict a compound’s availability to its target in cell tissue or in the brain. Novartis explored three HPLC assays using stationary phases analogous to blood and tissue, providing a rapid
screening technique for lipophilicity, tissue binding, and plasma binding. Linking these to brain free fraction and tissue distribution gives chemists a valuable tool to predict how their compounds will behave in biological assays.
3:20 Designing Bispecific Antibodies Targeting Angiogenesis for Improved Efficacy
Jijie Gu, Ph.D., Research Fellow, Immunology and Global Biologics, AbbVie Bioresearch Center
Angiogenesis is an important natural process of body used for wound healing and reproduction. Excessive angiogenesis occurs in more than 70 human disease conditions; growth of abnormal new blood vessels either feed diseased tissues as seen in cancer
and rheumatoid arthritis, or are leaky that lead to destroy of normal tissues in diseases such as diabetic blindness and wet age-related macular degeneration. Antiangiogenic therapies have demonstrated clinical benefit to treat some of these conditions.
In this talk, we will discuss examples (including clinical stage molecules) of designing novel anti-angiogenesis therapies against two angiogenic targets using DVD-Ig, a bispecific antibody technology, to further improve therapeutic effect
3:50 Close of Symposium