Dept Molecular Pharmacology & Biological Chemistry

Northwestern University Feinberg School of Medicine

303 E Chicago Ave, Mailcode W-896

Chicago, IL 60611

Email: d.m.watterson@gmail.com

D. Martin Watterson, PhD

Disclosures: NIH and foundation funding in the area of drug discovery; NU holds intellectual property and has licensed to industry novel CNS drugs developed in the speaker laboratory.

Session Overview

“Medicinal Chemistry Rules of Thumb, Myths and Realities in CNS Drug Discovery”

Educational goals:

Introduce the biology investigator to the rationale and scientific foundations of the “medicinal chemistry black box” aspects of the multi-disciplinary drug discovery and development process for CNS disorders.

Basics of Medicinal Chemistry for the Biologist

Deliverables:

Sufficient familiarity for better project planning, especially the potential to improve campaign risk management by addressing pharmacology fundamentals early in the process while the project has chemistry involvement.

The focus is on small molecule drugs due to the extensive state of knowledge about this class and their preponderance among approved drugs and pipelines; an emphasis on innovation and early proof of concept.

Lead Discovery and Optimization

Target ID and Validation

Clinical Trials

Preclinical Development

Regulatory Approval

Drug Discovery & Development Process Simplified

And a chemical

Need a target

(molecule or pathway/process)

Small molecule, peptide, protein, NA, etc: details of hit -> lead -> candidate differ based

on starting point & goals

Themes in Drug Discovery & Development Risk Reduction

Campaign risk often falls into two general areas - adverse pharmacology/toxicology (GLP preclinical/phase 1 clinical) or efficacy (phase 2-3 clinical):

related to target

related to the drug candidate (this session focus)Current approach - push failure earlier into the timeline:

Small molecule discovery/design -“smart chemistry”

fewer, more drug-like molecules

expand chemotype diversity within molecular property limits

Biological system -“smart biology”

early, non-GLP screens addressing risk in ICH guidelines

major barriers in the particular disease area

(eg CNS penetrance/distribution, undesired pharmacology)

“Kill early and fast” … “Fail fast in vivo”

= Identify major liabilities at start & address at discovery chemistry stage

Oral Blood/Brain Ratio Screen

In vivo efficacy in disease-relevant animal models

If YES, then GO If fail, then NO GO

If YES, then GO

Medicinal Chemistry Refinement Strategy

Concentration-dependent, selective activity screens

If NO, then NO GO

As needed,based on

outcomes

Activity Module

Non-GLP Pharmacological Module

Mini NOAEL with Increasing Dose

Informatics-driven Design (including Structure Assisted)

If YES, select candidate(s) for further development

Selected ADMET/PK related screens

GLP Preclinical studies

GMP production scheme

INDDevelopment Stage

Design & Synthesis Module

Physical Properties Characterization

Syntheses Using Established Chemistry

Contemporary Drug Discovery Engine: Biology Driven & Recursive

Adapted from Chico et al., (2009) Nature Reviews Drug Discovery 8:892

Pharmacokinetics (PK) of a drug reflect what the body does to the drug.

Pharmacodynamics (PD) reflects what the drug does to the body.

PD ≠ Efficacy; Efficacy reflects desired PD; Adverse Events reflect undesired PD, which are not necessarily toxicity.

Dosing is the pharmacological basis of therapeutics and includes:amount of drug administered (per body weight or volume).frequency of administration (e.g., once/day, weekly).duration of treatment (e.g., daily for one week; daily for life)initiation time window (e.g., ≤12 hrs injury; at MCI diagnosis)

Therapeutic index – a fundamental tenet of pharmacology is that all drugs have adverse effects at some dose. Dose range over which desired PD > undesired PD.

Details of dosing are key in targeting widely distributed targets or complex disorders, especially if disease is a state of perturbed homeostasis.

Working Definitions and Concepts

Molecular Properties, Tissue Barrier Permeation & Substrates

NOTE:

Molecules with the appropriate molecular features can be clinically useful even if the original molecular target is not the pharmacological mode of action for disease efficacy.

For a more detailed excellent case study, a suggested reading is:

“From basic science to blockbuster drug: the discovery of Lyrica” by Richard B. Silverman (2008) Angew. Chem. Int. Ed. 47:3500-3504.

This drug development campaign also provides example of how preclinical dosing analysis can provide insight into true molecular target for in vivo efficacy vs the target of design.

Molecular properties of a drug - physical characteristics that, in aggregate, contribute to how a molecule will alter, or be altered, in complex biological systems. Dr. Chico will address this fundamental issue in her lecture.

Caffeine is a natural product, a historical source of candidate drugs & alternative scaffolds

It is safe. A fatal dose is >10 grams => 80 to 100 cups of coffee in rapid succession. Accidental overdose is not an easy thing to do.

However, natural products are not inherently safer than engineered or synthetic products. e.g., - arsenic is a natural product.

Natural products are often multi-target drug candidates – good if appropriate; can be separated in medicinal chemistry refinement if necessary.

Dr. Koehn will address natural products as starting points in his lecture.

Natural Products: Historical Source, Alternative Chemical Space

Caffeine is a central nervous system stimulant and a diuretic.

Single drug - two in vivo pharmacological actions

Safety: “off label” use is not necessarily safe

Efficacy: The testing of an FDA approved drug for another disease indication requires addressing pharmacology, formulation and dosing issues. Risk for non-efficacy in clinical trials can increase if the existing drug does not have the appropriate properties for the new indication, thereby adversely impacting concepts in the field. e.g., a CNS disease trial of a kinase inhibitor drug approved for oncology, but lacking adequate BBB penetrance, potentially linked to molecular property profile, has more than one interpretation of failure.

Alternative Use & Reformulation of Existing Drugs

Drugs are approved by government regulatory agencies for a given disease indication, with consideration of dosing. The details of preclinical and clinical safety pharmacology and toxicology investigations can vary depending on the proposed disease use and dosing regime.

Chemotypes: Pharmacological Landscape with Diversification

Example of three related, heteroaromatic chemotypes found in nature.

Readily synthesized from inexpensive raw materials – cost of goods/scale.

All are amenable to chemical diversifications using established synthetic schemes.

Chemical diversification can yield either major changes in pharmacodynamics (PD) with minor chemical changes or small changes in PD while altering significantly the pharmacokinetics (PK).

“Steep” structure-activity landscape

e.g., chemist might “move” methyl group around ring to test if major impact on activity;

in this case, pharmacology is changed

SAR Landscape: Activity Change with Chemical Diversification

“Flatter” structure-activity landscape

e.g., “moving” methyl group around ring has little or no impact on activity

but might impact PK

no difference in activities

Simple chemical diversification = major changes in pharmacology? early feasibility tests to define potential character of scaffolds based on certain chemotypes

How Can SAR Landscape Impact Project Management?

Working with a compound that has a “flat” structure activity landscape:

Activity outcomes from chemical diversification might be more readily forecast, but major changes in activity/function may be difficult to evolve after a certain point. One might want to work with more than one chemotype in early discovery phase; potentially limit population of chemotype in library for activity screens?

Working with a compound for which feasibility date indicate a “steep” structure-activity landscape:

Chemical diversification at different atoms on the core chemotype could generate major improvements or loss of activity, and metabolites generated by first pass metabolism might generate even more active or toxic products. In these cases, % chemical similarity has little relationship to activity similarity; may be prudent to test early in campaign for metabolic stability potential and be alert for active metabolites; populate library with multiple versions of chemotype if diversifiable?

Example Scenarios:

Dr. Behanna’s lecture will summarize what one looks for in the chemist’s tool box when planning hit discovery and medicinal chemistry refinement campaign to leverage useful chemotypes

= injury to trauma center time gap

Injury Mechanism of Action (MOA) disease progression process

Later Neurologic Dysfunction Resulting from Earlier Stress

Process

Time

hours Weeks - Months- Years

Ch

ang

es in

en

dp

oin

ts

2 4 6 8 10 12

Dosing Considerations Will Impact Chemistry Project Management

Closed Head Injury Example: •Target processes changing within clinically relevant time window of treatment that impact longer term neurologic outcomes.• Non-oral administration route.

* Will treatment in this window yield desired downstream outcomes?

*

The interface of PK and PD is a critical planning issue, especially if disease progression modification is goal. Excessive focus on extended drug presence, if not needed for efficacy, can increase adverse event risk.

= drug levels

Smart Chemistry – recursive, driven by the biological goalIntegration of decision filters based on informatics (e.g., structure, chemistry and pharmacology) and feasibility screens (e.g., pharmacology, mechanism of action, therapeutic window, extended PD) in the early discovery process can:

- save time, cost and effort in the discovery/development process;- add discrete Go/No Go decision steps as the campaign progresses; - reduce risk in later stages.

 Themes and Caveats The scientific process is similar among small molecule medicinal chemistry efforts in drug discovery, with details defined by a particular campaign/disease area and the chemistry starting point (libraries and small molecule design).

- More is not better; either in chemical libraries or in synthetic efforts to solve medicinal chemistry refinement issues.

- Hits are generally not drugs – depending on chemical library focus, need to plan on extensive med chem refinement or reformulation/safety pharmacology for new use.

- Chemical biology is not drug discovery, but tool compounds used to demonstrate “druggability” can be useful starting point for scaffolds/chemotypes.

Summary: Risk Reduction by Leveraging Success

Laura Chico, PhDDesigning small molecules with increased potential for CNS

bioavailability.

 

Heather Behanna, PhDSynthetic chemistry essentials for biologists.

Frank Koehn, PhDNatural products as drug starting points.

I. Basics of Medicinal Chemistry

Designing small molecules with increased potential for CNS bioavailability

Laura Chico, PhD

Overview/Objectives

Addressing bioavailability is a critical first step in CNS drug discovery Bioavailability ~ drug available in the body to act at target ADME: Absorption, Distribution, Metabolism, Excretion Case studies – how bioavailability, metabolism can impact efficacy, safety

Molecular Properties 101 – what makes a drug act like a drug? Take-home message: incorporating molecular properties guidelines can help you

effectively prioritize your CNS drug discovery efforts

Applying the concepts – how can you select a more “CNS friendly” chemical library?

Identifying CNS drugs requires unique considerations beyond efficacy

BIOAVAILABILITY – drug available in the body to act at target Inability to reach target in sufficient amounts during appropriate time window LIMITS

opportunity for efficacy – BBB, metabolism, efflux Caveat: Bioavailability DOES NOT guarantee drug efficacy STARTING POINT: How does an oral drug get into the CNS?

Quantification

LogBB = comparison of brain, plasma concentrations

Relative bioavailability %F = [AUCpo] / [AUCiv]

Absorption

Metabolism

Tissue Distribution

Time

[Drug]

Molecular properties influence how drugs are absorbed, how they are distributed, how they interact with transporters and metabolizing enzymes