Property-Based Drug Design in Medicinal Chemistry

2015 Archived Content

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The drug discovery landscape is rapidly changing and with it comes the need to generate leads with lower attrition rate. Property-based drug design approach is guiding researchers in designing candidates with the right balance of physicochemical properties - safety and absorption, distribution, metabolism, and excretion (ADME) profiles. 4th Annual Property-Based Drug Design in Medicinal Chemistry conference will bring together experts and leaders from industry and academia to share strategies and case studies for new and non-traditional molecules, how computational modeling and data management can be used effectively, and to discuss novel ways to measure or predict properties to make molecules more drug-like and overcome challenges in discovery, development, and the clinic.

Thursday, June 11

12:00 pm Registration

2:00 Chairperson’s Opening Remarks

Gregory L. Warren, Ph.D., Senior Applications Scientist, OpenEye Scientific Software, Inc.

2:05 Keynote Presentation: Exploring Macrocycles for Drug Discovery: Novel Lead Series for Challenging Protein-Protein Interactions

Nick Terrett, Ph.D., CSO, Ensemble Therapeutics Corp.

Macrocycles are found widely in nature and several are marketed as drugs with good drug-like properties. This presentation will illustrate how Ensemble can rapidly generate millions of synthetic macrocycles using DNA-programmed chemistry, and how they are efficiently screened against protein-protein interaction targets to identify hit compounds and SAR. The novel approach will be illustrated with successful examples of lead discovery programs, including the discovery of novel XIAP and IL17A antagonists.

2:35 Property- and Fragment-Based Design Considerations for Protein-Protein Interaction Targets, a Case Study

Christopher N. Johnson, Ph.D., CChem FRSC, Director, Medicinal Chemistry, Astex Pharmaceuticals

Astex has successfully applied fragment-based drug design to protein-protein interaction targets. Key factors in this success have been (i) detailed structural understanding of binding interactions between fragment and target protein via x-ray crystallography and (ii) rigorous control of physicochemical properties. The approach is exemplified by Astex’s Inhibitor of Apoptosis Protein (IAP) project, where potent dual antagonists of XIAP and cIAP1 were identified, having in vivo anti-tumor activity.

3:05 Computational Design for Improving ADME Properties of Peptidic Macrocycles

Alan M. Mathiowetz, Ph.D., Director, Worldwide Medicinal Chemistry, Pfizer, Inc.

A great deal of progress has been made in recent years in elucidating design principles for achieving favorable ADME properties in Beyond Rule-of-5 macrocycles. Many of the important principles, such as minimization of exposed polar surface area to improve permeability, are dependent upon the overall 3D structure, which can be computationally predicted and confirmed experimentally. Here we present computational approaches and property/ADME trends seen in a variety of interesting macrocyclic chemotypes.

3:35 A Delicate Balancing Act: Applying Property Filtering to Fragment Replacement in BROOD

Warren_Gregory Gregory L. Warren, Ph.D., Senior Applications Scientist, OpenEye Scientific Software, Inc.

Lead optimization is not a simple one-dimensional optimization of affinity and effective computational tools should allow of optimization of other molecular properties. We will present BROOD v 2.1 a fragment-based R-group and template replacement lead optimization application that can suggest replacement groups that are simultaneously optimized for many different properties at once. Several examples to demonstrate this unique ability will be presented.

4:05 Refreshment Break in the Exhibit Hall with Poster Viewing

4:45 Optimizing Brain Exposure in CNS Drug Discovery

Ruben Alvarez Sanchez, Ph.D., Head, Pharmaceutical Profiling, Drug Disposition and Safety, F. Hoffmann-La Roche

For drugs actively transported across the blood-brain barrier, unbound plasma and unbound brain concentrations differ to an extent that is commonly unknown. We report on approaches to assess and predict unbound brain concentration for P-gp substrates and how they can be utilized in early CNS drug discovery to enhance the understanding of PK/PD relationships and support a clinically meaningful compound optimization.

5:15 Inhalation by Design: Approaches towards Designing Drug Candidates for Lung Diseases

Peter Jones, Ph.D., Senior Principal Scientist, Medicinal Chemistry-Inflammation and Remodelling, Pfizer, Inc.

Designing compounds with suitable properties for inhalation present unique challenges to the medicinal chemist. This talk will discuss a number of programs from within Pfizer that have addressed this issue, across numerous target classes, to produce inhaled candidate drug molecules for the treatment of various lung diseases – Inhibition of GPCRs, PDEs and Kinases have been targeted successfully via this approach.

5:45 Discovery of Asunaprevir (BMS-650032): An Approved NS3 Protease Inhibitor for the Treatment of Hepatitis C

Paul Scola, Ph.D., Research Fellow & Group Leader, Department of Virology Chemistry, Bristol-Myers Squibb Research Co.

Hepatitis C Virus (HCV) infection is an insidious liver disease that affects more than 170 million people worldwide. The HCV NS3/4A protease is an essential enzyme for viral replication and, as such, has been validated as a target for anti-HCV therapy in clinical trials. In this presentation, the discovery of BMS-650032, a potent and selective inhibitor of the NS3/4A enzyme, recently approved for treatment of HCV, will be described. Highlights of this discovery process include the design of the acylsulfonamide chemotype, as well as optimization of ADME and toxicology properties within this chemical series.

6:15 Close of Day

Friday, June 12

7:30 am Interactive Breakout Discussion Groups with Continental Breakfast

Each discussion group in this session is led by a moderator/s who ensures focused conversations around key issues. Attendees join a specific group and the small, informal setting facilitates sharing of ideas and active networking.

TABLE 14: Strategies for Obtaining a Balance among Competing ADME Properties (Solubility, Clearance, Permeability) In Beyond Rule-Of-5 Molecules

Moderator: Alan M. Mathiowetz, Ph. D., Director, Worldwide Medicinal Chemistry, Pfizer, Inc.

Is there an optimal logD range for molecules larger than 500 Daltons, that provides the best opportunity for a good balance of properties?
What strategies, other than lowering logD, are good for reducing clearance in high MW, high logD, compounds?
Is macrocyclization generally advantageous for achieving a good balance of ADME properties or is it detrimental?

TABLE 15: Use of Physicochemical Properties in the Early Prediction of Drug Promiscuity

Moderator: John Reilly, Ph.D., Senior Research Investigator, Global Discovery Chemistry, Novartis Institute of Biomedical Research

Is high cLogP or cLogD7.4 a good enough early descriptor for compound promiscuity?
If not what predictive philosophies or experimental methodologies do you undertake in early prediction of drug promiscuity?
What are the confidence levels of predictive computational models for drug promiscuity and what methods do you currently outsource?

TABLE 16: Ligand Efficiency Metric (LEMs)

Moderator: Peter Kenny, Ph.D., Visiting Scientist, NEQUIMED-IQSC, University of São

What do we mean when we say that Ligand Efficiency normalizes affinity with respect to molecular size?
What assumptions are we making when we use Ligand Efficiency and Lipophilic Efficiency?
Should we normalize potency by logP or logD when using Lipophilic Efficiency?

8:35 Chairperson’s Remarks

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

8:45 FEATURED PRESENTATION: PROPERTYBASED MOLECULAR DESIGN: WHERE NEXT?

Peter Kenny, Ph.D., Visiting Scientist, NEQUIMED-IQSC, University of São

I will draw the distinction between hypothesis-driven and prediction-driven molecular design before questioning some of the assumptions commonly made in drug discovery. Alternatives to the octanol/water partitioning system will be discussed and relationships between structures will be outlined as a framework for analyzing biological activity and physicochemical properties.

9:15 Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates

Jan Kihlberg, Ph.D., Professor, Department of Chemistry, BMC, Uppsala University, Sweden

Analysis of drugs and clinical candidates having MW >500 Da demonstrate significant opportunities for discovery of cell permeable and orally bioavailable drugs in physicochemical space far beyond the rule of 5 (bRo5). As compared to Ro5 compliant drugs, those bRo5 may modulate different kinds of targets, in particular ones having flat and groove shaped binding sites. Interestingly, macrocycles appear to have features that provide special opportunities in bRo5 drug space.

9:45 Phosphatidylcholine Affinity Chromatography and Link to Compound Promiscuity, Non-Specific Binding and Phospholipidosis Assessment

John Reilly, Ph.D., Senior Research Investigator, Global Discovery Chemistry, Novartis Institute of Biomedical Research

In this work, a high throughput chromatographic phosphatidylcholine (PC) affinity assay has been demonstrated to offer an insight into the prediction of compound promiscuity, non-specific binding and phospholipidosis-inducing potential (PLIP) of pharmaceuticals. Results will include >1000 compound study comparing PC affinity to generic compound promiscuity "Target Hit Rate" assay and the benefit of this approach over cLogP. Results will also be presented on how his assay has been a useful tool to predict for non-specific binding for PET ligand tracers and PLIP.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

11:00 Known Unknowns in Drug Discovery Data

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

Data drives Drug Discovery research at all levels and determine the outcome of many thousands of decisions that govern the progress, success, or failure of any one project. Yet, even the ‘experimental’ error of this data is often unknown, under-utilized, or unconfirmed and the actual error has been shown to be even larger that that. This includes physical property data as well as that from assays, biomolecular structure determination, and computational modeling. These errors, their magnitude and genesis will be discussed with a eye toward informed decision making.

11:30 Physicochemical and Biomimetic Properties to Guide Lead Optimization

Klara Valko, Ph.D., DSc, FRSC, Senior Scientific Investigator, UK Analytical Chemistry, RD Platform Technology & Science, GSK

Measurements of physicochemical and biomimetic properties in early drug discovery are used for the estimation of in vivo distribution and drug efficiency. The Drug Efficiency Index (DEI) (potency plus drug efficiency) has been shown to be proportional to receptor occupancy. Simultaneous optimization of potency and drug efficiency can help guide candidate selection toward compounds of increased quality and with reduced chance of later stage failures.

12:00 Hepatobiliary Drug Transport: Predicting and Optimizing Pharmacokinetics

Manthena Varma, Ph.D., Senior Principal Scientist, Pharmacokinetics Dynamics & Metabolism, Pfizer, Inc.

Hepatobiliary transport is a major disposition pathway, and estimating its contribution to the total systemic clearance is extremely valuable for predicting clinical pharmacokinetics and understanding the possible mechanisms of hepato-biliary toxicity and potential drug-drug interactions. Furthermore, the clinical importance of hepatic drug transporters has attracted potential design strategies to support liver targeting – a key approach to maximizing the potential therapeutic index of a compound. Early assessment of drug exposure (PK) is challenging in this space given the limited information regarding the specific transporter expression levels, lack of established IVIVE and lack of sizable datasets. This presentation provide insight into the hepato-biliary transport with relevance to exposure optimization and the current understanding of the physicochemical and structural drivers in order to facilitate rational drug design.

12:30 Sponsored Presentation (Opportunity Available)

12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:30 Session Break

2:00 Chairperson’s Remarks

Robert S. Foti, M.S., Senior Scientist, Pharmacokinetics & Drug Metabolism, Amgen, Inc.

2:05 A Systems Pharmacokinetics Approach to the Optimization of Drug Properties to Help Maximize Therapeutic Index: On the Quantitative Prediction of Unbound Tissue Distribution and its Implication for Drug Design

Avijit Ghosh, Ph.D., Director, Mechanism Based Drug Disposition Pharmacodynamics and Metabolism, Janssen R&D

In this work, we leverage a mathematical model of the underlying physiochemical properties of tissues and physicochemical properties of molecules to support the development of hepatoselective glucokinase activators. A case study using this approach in the development of hepatoselective glucokinase activators via organic anion-transporting polypeptide–mediated hepatic uptake and impaired passive distribution to the pancreas is described.

2:35 Utilizing Physiologically Based Pharmacokinetic Modeling to Inform Formulation and Clinical Development

Robert S. Foti, M.S., Senior Scientist, Pharmacokinetics & Drug Metabolism, Amgen, Inc.

Physicochemical properties and early ADMET 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 formulation.

3:05 The Discovery and Development of an HIV-1 Attachment Inhibitor Clinical Candidate

Kap-Sun Yeung, Ph.D., Principal Scientist, Discovery Chemistry, Pharmaceutical R&D, Bristol-Myers Squibb Co.

The inhibition of the attachment of the HIV-1 viral glycoprotein gp-120 to the host cell receptor CD4 during the first step of the viral entry represents a novel antiretroviral approach. This talk will discuss the modifications made by medicinal chemists based on clinical feedback from multiple compounds, discuss a successful prodrug approach, and describe formulation development leading to a clinical candidate that is currently progressing to Phase III studies.

3:35 Close of Conference