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The Rise and Fall of Natural Product-based Pharmacology

: How the Pharmaceutical Industry Mucked Everything Up
by

Christopher Regnery

on 4 April 2014

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Transcript of The Rise and Fall of Natural Product-based Pharmacology

Drug - any chemical substance used for the
treatment, cure, prevention, or diagnosis of a
disease
FDA Approved
Natural Products
Synthetic Compounds
chemical substance produced
by living organism, with
pharmacological activity
chemical substance produced
synthetically de novo (from the
beginning)
(Natural products as sources of new drugs, Newman & Cragg, 2012)
Natural Products
Synthetic Compounds
Drug Discovery
Lead compounds or 'hits'
Activity/Selectivity
Development
Drug Formulation
ADME/T
Activity - Drug-Target binding
Selectivity - Promiscuity of Drug
Absorption
Distribution
Metabolism
Excretion
Toxicity
'druglikeness' or 'drug-like' properties
Is it a 'good' lead compound?
Pharmacokinetics -
what the body does to the drug
Pharmacodynamics -
what the drug does to the body
The Druglikeness Model is Built
WDI
50,000 Drugs
and Drug Candidates
8,548 Named Compounds (out of 50,000)
Building the USAN (Lipinski) set
2,287 Compounds
with clinical exposure
no known biological transporters
USAN (Lipinski) Set
USAN Set - Good Drug Candidates
2,287 Compounds
What do they have in common?
4 Molecular properties =
key drug-like properties
Molecular Weight
Lipophilicity
H-Bond Donors
H-Bond Acceptors
Greater than 500 Da
11% of USAN set
cLogP > 5
10% of USAN
NHs + OHs > 5
8% of USAN
Ns + Os > 10
12% of USAN set
Rule of Five is born!
No More Than One Violation Of:
MWT > 500 Daltons
cLogP > 5
H-Bond Donors (OH, NH) > 5

H-Bond Acceptors (O, N) > 10
USAN Set (Properties Outside the Cutoff)
HBD + HBA = 10%
HBA + MWT = 7%
HBD + MWT = 4%
MWT + LogP = 1%
(Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Lipinski et al., 2001)
Phase II (or further)
Phase II
Combinatorial Chemistry
(circ.ahajournals.org)
The Rise and Fall of Natural-Product based Pharmacology
How The Pharmaceutical
Industry Mucked
Everything Up
by Christopher M. Regnery
Yamatetan
Pansporin
Firstcin
Ajicef
Sepatren
Cefrom
Banan
Cefzil
Takesulin
Fortam
Tomiron
Seftem
Epocelin
Rocephin
Zinnat
Cosmosin
Klaricid
Synercid
Nortron
Finibax
Invanz
Erasis
Flumarin
Ritro
Farom
Zienam
Varacillin
Lorabid
Merrem
Shiomarin
Carbenin
Synercid
Mycobutin
Normix
Rifampin
Rifacol
Ricamycin
Rulid
Unasyn
Tazocillin
Ketek
Temopen
Tygacil
Hevizos
Famvir
Cymevene
Imunovir
Epivir
Vectavir
Usevir
Zerit
Viread
Valtrex
Valcyte
Hivid
Retrovir
Agenerase
Reyataz
Prezista
Vitravene
Lexiva
Crixivan
Natural Products-Based
Lipitor
Zalig
Amasulin
Cubicin
Monourillsepacin
Sagamicin
Miocamycin
Bactroban
Netromicine
Targocid
Lumota
Habekacin
Doyle
Fortimicin
Sunamed
Azactam
Omegacin
Tomiporan
Flomox
Cegzon
Meiact
Maxipime
Globocef
Cefspan
Tacef
Meicelin
Neucef
Monocid
Cefobis
Precef
Wincef
Kaletra
Kaletra
Viracept
Norvir
Invirase
Aptivus
Artemisin
Mectizan
Artemotil
Artemetheri
Arinate
Ornidyl
Fansimef
Mepron
Aablaquin
...
Combinatorial-Based (Synthetic)
Nexavar
Drugs Approved by the FDA 1981-2006
(chrisregnery.com)
Synthetic process to generate libraries of thousands of compounds, very quickly
83% of NP motifs absent from
combinatorial libraries
Building Better Natural Product Libraries
Maximize efficiency by improving
NP libraries vs. Synthetic libraries
Drug-like physiochemical properties
Only 22% of NPs in DNP aren't RO5-compliant
High-throughput Screenable
Breadth of Natural Product chemical space
(Drug-like Properties: Guiding Principles for the Design of Natural Product Libraries, Camp et al., 2012)
Natural Product Screening Library
lead-like: more stringent drug-like properties
MW < 350 Da (vs. < 500 Da)
Lipophilicity
used as first filter
resisted molecular property inflation ("Lord of the Rules")
Retain Natural Product extracts w/ log P > 5
Elute Natural Product extracts w/ log P < 5
Drugs:
Natural
Synthetic
Which Is More Drug-Like?
Lipophilicity
Molecular Weight
Donors & Acceptors
Natural Products vs. Synthetic Compounds
Natural Products and Drugs operate
in a similar physiochemical space

are more diverse
Combinatorial Compounds are
not very similar

not using enough 'druggable' space
cLogP and molecular mass trends (1965-2007)
(The influence of drug-like concepts on decision-making in medicinal chemistry, Leeson & Springthorpe, 2007)
Drug approvals decline as fewer drugs launched with low
molecular mass (<350 Da)
cLogP trends in four different pharmaceutical
companies
Molecular mass trends in four different
pharmaceutical companies
Lead-like Enhanced Fractions (LLE Fractions)
RP-HPLC used for fractionation of LLE Extracts
Decision gate used to allow some NPs with high MW in the library (Taxol)
SPE
Crude NP Extract
'Decision Gate'
Bioanalysis (Malaria and human African trypanosomiasis (HAT)
Physiochemical Property Histograms
Malaria
HAT
Chemical Space
space that encompasses all theoretical compounds
'infinitely' vast
limited to < 500 MW
only few of the most common atoms in drugs
Drug-like chemical space
10
200
compounds
SciFinder: compounds
Natural products show better activity and selectivity
than can be achieved by synthetic drugs
(Natural Product Chemistry for Drug Discovery, Buss & Butler, 2010)
FDA Drug Approvals per year
No More Than One Violation Of:
MWT > 500 Daltons
cLogP > 5
H-Bond Donors (OH, NH) > 5

H-Bond Acceptors (O, N) > 10

Natural Products are an
exception
The Exception to the Rule of Five
Natural Products are orally
bioavailable even when they
shouldn't be!
Natural Product Woes
Difficulty in access and supply
Inherent complexity
Slow to work with
Intellectual property right concerns
Aspirations associated with synthetic
libraries
90% Attrition Rate
Pitfalls of Big Pharma
30% Profitability
=97% of drugs/drug candidates
cost more than worth
Average out-of-pocket cost of bringing
1 drug to market:
~$800 million
Drug Candidates, by source
Better Lead Compounds
Better Drug Candidates
= Better Drugs
Natural Products vs. Synthetic Compounds
The Final Showdown
So why did Merck shut down all natural
product research in 2008?
Diversity-Oriented Synthesis
(Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules, Galloway et al., 2010)
7
A Solution for Pharmaceutical Science?
Why Pills?
Most popular dosage form
66% of all prescription drugs
High patient compliance
Low manufacturing/storage costs
Safest route of administration
(Drug-like Properties, Kerns & Di, 2008)
(Drug-like Properties, Kerns & Di, 2008)
FDA Drug Approval Phases
cern-foundation.org
Discovery to market: 14 years
And Now?
30% Decrease in NP Research (2001-2008)
Evolution vs. Combinatorial Chemistry
Mother Nature
unlimited' access to reagents/mechanisms
billions of years
natural selection
Combinatorial Chemistry
known reagents/mechanisms only
a few decades
random chance
Does only one synthetic drug mean a failure
or a success?
Shift focus from compound generation to library generation
Academic/Commercial Licensing
Sharing of information = everybody wins!
Incentivize Natural product libraries
Lead-Like Enhanced Extracts (LLE)
Generated randomly
oral bioavailability
safety
Lipinski Revolutionizes Druglikeness
Benefits
How They Made It
backdoor approach
set of good drug candidates
evaluate common properties
key drug-like properties
Weed out bad drugs early
Improve: 90% Attrition
$800 million price tag
Defines key drug-like properties
Target Audience?
99% of good drug candidates: MW < 500, LogP < 5
Molecular property inflation
Not seen in drugs
MWT + LogP = 1%
Pre-HTS (NP era)
Post-HTS (Combinatorial era)
"Lord of the Rules"
Property Histograms Principal Component Analysis (PCA)
10
= lots of 'druggable' space left
Chinese Medicine
When in doubt, look to
natural products!
Addressing the Concerns
RO5 Compliant
Lipophilicity Filter
Molecular Weight Filter
SPE for extraction of lead-like enhanced extracts
RP-HPLC
HTS
Have the concerns been addressed?
Lipophilicity Filter
Removing NP extracts with LogP > 5
Physiochemical Property Histograms
Malaria
HAT
Molecular Weight Filter
Removing NP extracts with MW > 500 Da
(Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Lipinski et al., 2001)
(Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Lipinski et al., 2001)
(Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Lipinski et al., 2001)
(Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Lipinski et al., 2001)
(Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Lipinski et al., 2001)
(The influence of drug-like concepts on decision-making in medicinal chemistry, Leeson & Springthorpe, 2007)
(The influence of drug-like concepts on decision-making in medicinal chemistry, Leeson & Springthorpe, 2007)
(The influence of drug-like concepts on decision-making in medicinal chemistry, Leeson & Springthorpe, 2007)
(Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Lipinski et al., 2001)
(Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry, Fehrer & Schmidt, 2003)
Combinatorial
Compounds
Drugs
Natural
Products
(Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry, Fehrer & Schmidt, 2003)
(Characterization and Comparative Analysis of Chemical Libraries for Drug Discovery, Qiang et al., 2012)
Chinese medicine
(Drug-like Properties: Guiding Principles for the Design of Natural Product Libraries, Camp et al., 2012)
(Drug-like Properties: Guiding Principles for the Design of Natural Product Libraries, Camp et al., 2012)
(Drug-like Properties: Guiding Principles for the Design of Natural Product Libraries, Camp et al., 2012)
(Drug-like Properties: Guiding Principles for the Design of Natural Product Libraries, Camp et al., 2012)
(Drug-like Properties: Guiding Principles for the Design of Natural Product Libraries, Camp et al., 2012)
(Drug-like Properties: Guiding Principles for the Design of Natural Product Libraries, Camp et al., 2012)
Nexavar (Sorafenib)
logP: 4.759
MW: 464.831
HBA: 7
HBD: 3

RO5 Analysis
kidney and liver cancer
1.3% of out-of-pocket revenue spent on small molecule drug discovery
Lipitor (Atorvastatin)
logP: 5.345
MW: 558.65
HBA: 7
HBD:
4

RO5 Analysis
high cholesterol
molinspiration.com
molinspiration.com
but because its a NP...
2 violations
The Broad Institute (MIT/Harvard)
non-profit
full library licensing
Pfizer/Washington University School of Medicine
academia + industry
licensing out past and current drug candidates
Acknowledgements:
no one but myself
Dr. William Bartlett
Nicholas Gearheart
Dr. Meredith Harker
Allex McDaniel
Dr. Kennelworth Miller
Dr. John Rakus
Deborah Regnery
Patrick Regnery
Wesley Surta
Marcus Warriner

The entire FLC Chem Department!
circ.ahajournals.org
But there were 35 new drugs approved in 2012!
Not exactly...
Not all NME

FDA trying to paint a rosy picture
justify Prescription Drug User Fee Act (PDUFA)

(Fresh from the biologic pipeline, Kling, 2010)
Taxol (Paclitaxel)
logP: 4.945
MW: 853.918
HBA: 15
HBD: 4

RO5 Analysis
cancer chemotherapy
molinspiration.com
but because its a NP...
2 violations
Full transcript