Property-Based Drug Design Conference - Day 2



Friday, May 23

7:30 Interactive Problem Solving Breakout Discussion with Continental Breakfast

This interactive breakfast session provides conference delegates and speakers an opportunity to brainstorm and exchange ideas around a specific topic. This format allows participants to network, meet potential collaborators, vet ideas with peers, and be part of a group problem-solving endeavor.

Table 1: Physical and Biological Properties of Pharmaceuticals: What Do We Worry About and When Do We Start Worrying?

Moderator: Terry Richard Stouch, Ph.D., President, Science for Solutions, LLC

• What properties should we worry about and at what stages of discovery and development?
• Is compound profiling too early in discovery killing promising leads?
• When does not worrying enough result in difficult or impossible liabilities at late stages?
• What properties can be successfully engineered out of a compound at later stages?
• What properties should kill a compound and its subsequent series early on?

Table 2: Which Small-Molecule Properties are Critical and Why Should We Care About Them?

Moderator: Steven LaPlante, Ph.D., Adjunct Professor, Institut National de la Recherche Scientifique (INRS) University; Founder & CEO, NMX Research & Solutions

• What are the most important compound properties and why they should be addressed?  What are the root sources of these properties??
• What are known (or suspected) structure-property relationships?
• Can compound properties be implicated in or the cause of some drug side-effects?

Property-Based Design for Developability 

8:35 Chairperson’s Remarks

Terry Richard Stouch, Ph.D., President, Science for Solutions, LLC

8:45 FEATURED PRESENTATION: Understanding Solid State Structure and Properties that Underpin Developability

Sarah PriceSarah L. Price, Ph.D., Professor of Physical Chemistry, Department of Chemistry, University College London

The drug product often contains a crystalline form of the drug molecule, and when the drug is delivered in another phase, crystallization has to be avoided. Although we do not yet understand all the factors which determine the outcome of crystallisation processes, current computational methods of searching for the thermodynamically feasible structures can already provide a useful complement to polymorph screening, providing insight into the possible complexities of the solid state.

9:15 The Potency-Insolubility Conundrum in Drug Discovery: Mechanism and Solution

PatrickConnellyPatrick R. Connelly, Ph.D., Principal Scientific Fellow, Vertex Pharmaceuticals, Inc.

The potency-insolubility conundrum has led to innumerable failed drug discovery efforts. By examination of the high resolution structural and high precision thermodynamic properties of telaprevir, it is revealed that potency and insolubility share a common origin. The work is explored in the broader context of a new strategy for drug discovery and pharmaceutical development termed Translational Drug Development. Applications of materials chemistry to overcome the potency-insolubility conundrum in the development of recently approved drugs for hepatitis C and cystic fibrosis are presented.

9:45 Optimizing Solid-State Properties for Development

HarveyLiebermanHarvey Lieberman, Ph.D., Senior Manager, Analytical Research & Development, Sanofi

Discovery programs generally concentrate on producing drug candidates with suitable potency, selectivity and ADME properties, and aspects of the solid-state are dealt with once the molecule has entered Development. Physicochemical properties of the solid-state can impact solubility, stability and processability leading to increased costs and timelines. The aim of this presentation is to highlight features that may be assessed at a stage of late Discovery or early Development in order to mitigate the risk.

10:15 Coffee Break in Exhibit Hall with Poster Viewing

11:00 Use of Prodrugs to Advance Promising Molecules into Development

RebeccaNofsingerRebecca Nofsinger, Ph.D., Senior Research Pharmacist, Biopharmaceutics Group, Merck & Co., Inc

Prodrugs can be considered a way to optimize the biopharmaceutical properties of a drug molecule. An ideal prodrug is not active and is efficiently converted to the active molecule, via an in vivo chemical or enzymatic transformation, ultimately enabling delivery of the active molecule at efficacious levels without adverse effects. General prodrug strategy will be outlined and a case study highlighting prodrugs made to enhance the colonic absorption of a promising compound will be presented.

11:30 Exploiting Drug Solution Properties to Improve Discovery and Development Processes –Importance of Aggregation, Solubility, Atropisomerism and Bioactive Conformations

StevenLaPlanteSteven LaPlante, Ph.D., Adjunct Professor, Institut National de la Recherche Scientifique (INRS) University; Founder & CEO, NMX Research & Solutions

The behavior of drugs in solution impacts all levels of drug discovery and development. Revealing the various types of behaviors is a key step toward significantly improving drug discovery processes such as screening, triaging, lead optimization and development. Knowledge of these phenomena should help to minimize the costly advancement of promiscuous and unstable drug candidates. Examples to be discussed include the wide-spread phenomenon of drug aggregation and the equilibrium with soluble free-molecules. Other examples address free-state bioactive conformation and conformation-based atropisomer chiraility.

12:00 pm Luncheon Presentation (Sponsor Opportunity Available) or Lunch on Your Own

12:30 Session Break


12:55 Chairperson’s Remarks

Jan Wahlstrom, Ph.D., Director, Pharmacokinetics & Drug Metabolism, Amgen, Inc.

1:00 FEATURED PRESENTATION: Predicting Pharmacokinetics through the Integration of Physicochemical Properties and Physiologically-Based Modeling

Jan WahlstromJan Wahlstrom, Ph.D., Director, Pharmacokinetics & Drug Metabolism, Amgen, Inc.

Physicochemical properties and early ADME assays guide chemotype evaluation and rational scaffold alteration. This presentation will focus on the integration of these approaches with physiologically based pharmacokinetic modeling (PBPK) to enable the prediction of clinical outcomes and to optimize selection of development candidates.

1:25 Between a Rock And a Hard Place – Balancing Permeability & Solubility Characteristics to Identify Clinical Candidates

DarrenMckerrecherDarren McKerrecher, Ph.D., Associate Director, Medicinal Chemistry, Oncology iMED, AstraZeneca

The talk will review examples of strategies to use property-based design to optimise pharmacokinetic properties of lead candidates by balancing absorption and solubility profiles. Particular attention will be paid to strategies to control lipophilicity, to disrupt crystal packing to improve solubility, and to control of hydrogen bond donor count to improve permeability.

1:50 Deuterium in Drugs: Complexity in Pharmacokinetic Application

Alfin D.N. Vaz, Associate Research Fellow, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc.

Targeted substitution of hydrogen by deuterium in drug structures has the potential to alter drug pharmacokinetics. For any drug, the process requires a clear understanding of its systemic clearance mechanism, its metabolite profile, the enzymes and their reaction mechanisms involved in the primary metabolic clearance event, and species differences in systemic clearance. Examples will be discussed where cytochromes P450, monoamine oxidases, and aldehyde oxidases, play substantial roles in metabolism.

2:15 Practical Permeability Based Hepatic Clearance Classification to Simplify Complex Permeability, Transporter and Metabolism Interplay in Drug Discovery

PeterFanPeter Fan, Ph.D., Scientist, DMPK, Genentech, Inc.

We have developed a systematic approach in the form of a decision tree to help drug discovery scientists understand in vitro-in vivo clearance prediction disconnect by incorporating apparent permeability data generated from Mardin-Darby Canine Kidney (MDCK) cells and hepatocyte uptake data for new chemical entities. A new classification system is also introduced that can categorize and simplify the complex permeability, transport and metabolism interplay in the liver.

2:35 Beyond Red, Yellow and Green: Optimizing Drug Developability Using Model-Based Methods in Discovery

ArijitChakravartyArijit Chakravarty, Ph.D., Senior Scientist II, Modeling and Simulation, DMPK, Takeda Pharmaceuticals

Developability issues frequently derail drug development. A common approach to lead optimization is to improve physicochemical parameters (such as aqueous solubility or lipophilicity) individually, using arbitrary cut-off values. In my presentation, I discuss the limitations of this approach, and present integrated in vitro/in vivo/in silico approaches to integrate physicochemical parameters to provide a ‘look ahead’ at the net impact of chemical modifications on overall bioavailability, and to provide a way to proactively manage dose burden.

3:00 End of Conference


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