Discovery of innovative small molecule therapeutics

Full text of DOI:10.1021/jm8012823

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J. Med. Chem. 2009, 52, 2–9
2008 Alfred Burger Award Address
in Medicinal Chemistry
Discovery of Innovative Small Molecule Therapeutics
Magid Abou-Gharbia†
Center for Drug DiscoVery Research, School of Pharmacy, Temple UniVersity, 3307 North Broad Street, Philadelphia, PennsylVania 19140
ReceiVed October 9, 2008
Opening Remarks
advances in technology have enabled the pharmaceutical
industry to explore multiple medicinal chemistry approaches
in support of chemical biology efforts and to identify leads and
optimize drug candidates. These advances include improvements
in structure-based design, integrating X-ray crystallography,
computational chemistry, nuclear magnetic resonance spectros-
copy, multivariate analysis, parallel synthesis, and early phar-
maceutical profiling. Application of these techniques, coupled
with the growing field of biosynthetic engineering, precise
synthetic methods, and the use of high-resolution analytical
tools, has also spurred renewed interest in natural-product-based
drug research.
I’m honored and privileged to receive the prestigious Alfred
Burger Award in Medicinal Chemistry and to join the list of
distinguished individuals who received this honor before me. I
regard this award as a reflection and recognition for the efforts
of my research teams at Wyeth Research, for their creativity
and dedication over the years, and for the contributions of many
talented partners and collaborators who have made it possible
for me to receive this important award. Over the years I have
benefited from the advice and wisdom of many inspiring
mentors and role models and am deeply indebted to all of them.
I share with you my journey working in Drug Discovery at
Wyeth at the four discovery research sites over the past 2
decades and reflect on the evolution in medicinal chemistry
approaches that have been successfully utilized in discovering
today’s innovative drugs.
This lecture will give a brief overview of various medicinal
chemistry approaches from the past to present that we utilized
successfully to discover several marketed drugs and clinical
candidates. These approaches include the following sections:
(1) Ligand-Based Design, (2) Discovery of CNS Drug Candi-
dates, (3) Multidimensional Lead Optimization, (4) Pharma-
ceutical Profiling, (5) Structure-Based Design, (6) Natural-
Products-Based Drug Design, (7) Future Outlook.
Introduction
Today’s innovative drug discovery is costly and time-
consuming, with very few novel therapeutics making it to the
market place. Traditional medicinal chemistry approaches
adopted during the 1970s and 1980s were focused primarily on
analoguing of endogenous ligands and industry leads.1 Chem-
istry was low throughput and done iteratively, driven primarily
by biochemical observations derived from animal testing. In
contrast, the past decade has witnessed an evolution in medicinal
chemistry approaches wherein automation has been effectively
utilized in the synthesis of large numbers of analogues (com-
binatorial chemistry) and in the rapid screening of large numbers
of compounds (HTSa).2,3
At the turn of the century, subsequent to identification and
characterization of large numbers of targets, the deciphering of
the human genome led to an explosion in the “-omics”
technologies. The assimilation of the resulting information and
correlation of potential therapeutic targets with human diseases
present tremendous challenges for drug research. Nonetheless,
Ligand-Based Design
Ligand-based design, also referred to as pharmacophore-based
design, capitalizes on the presence of existing structural similari-
ties between a set of compounds and active ligands. The sources
of active ligands vary and include literature, patents, and in-
house experimental data of earlier lead compounds. This
approach usually provides a good starting point for the chemist
where the selected set of compounds is often more active than
randomly selected compounds. The power of the pharmacoph-
ore-based approach for lead generation lies in its ability to
identify diverse sets of compounds potentially possessing a
desired biological activity but having different chemical scaf-
folds. This approach has been used extensively in the discovery
of CNS therapeutics.
†
Contact information. Phone: (215) 707-4949. Fax: (215) 707-4701.
Discovery of CNS Drug Candidates
E-mail: aboumag@temple.edu.
a Abbreviations: 5-HT1A, 5-hydroxytryptamine subtype 1A; 5-HT2,
5-hydroxytryptamine subtype 2; 8-OH-DPAT, 8-hydroxy-2-(di-n-propy-
lamino)tetralin; AD, Alzheimer’s disease; ADME, absorption, distribution,
metabolism, and excretion; ADMET, absorption, distribution, excretion, and
toxicity; AIDS, acquired immune difficiency syndrome; BACE, ꢀ amyloid
converting enzyme; CNS, central nervous systerm; CoMFA, comparative
molecular field analysis; CYP, cytochrome P450; D2, dopamine subtype
2; EPS, extrapyramidal side effects; HTS, high throughput screening; NCE,
newchemicalentity;NMR,nuclearmagneticresonance;SAR,structure-activity
relationship; SPR, structure-property relationship.
Design of therapeutics for treatment of CNS disorders has
evolved from the early serendipitous discovery of chlorprom-
azine and benzodiazepine to current approaches utilizing ligand-
based design. Alterations in biogenic amine neurotransmitter
levels in the brain have been implicated in the pathophysiology
and pharmacotherapy of a number of neurological and psychi-
atric disorders.4 Over the years, the biogenic amines have
10.1021/jm8012823 CCC: $40.75
2009 American Chemical Society
Published on Web 12/10/2008

Award Address
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 1
Scheme 1. Structural Evolution of Effexor
3
Figure 1. Biogenic amines as a starting point for drug design.
conditioned avoidance responding in rats and monkeys without
inducing catalepsy.8,9 Compounds 1 and 2 demonstrated antip-
sychotic activity in schizophrenic patients in phase II clinical
trials.10,11 An alternative approach that we pursued for balancing
the paradoxical dopaminergic activity in the cortical and limbic
systems was to identify D2 partial agonists.12 CoMFA-driven
SAR studies directed toward discerning the D2 receptor agonist
pharmacohore and topography identified two advanced series,
the 7-hydroxyaminochromans (7-OH-AMC) and the 7-hy-
droxyaminobezodioxans (7-OH-AMB),13 and ultimately led to
the discovery of the D2 partial agonist Aplindore14 (DAB-452,
3). Compound 3 demonstrated potent dopamine D2 receptor
affinity and intrinsic activity between those seen with full
agonists and the antagonist aripiprazole in a variety of in vitro
assays and in an in vivo model of dopamine agonism. We
hypothesized that the level of intrinsic activity seen with 3
should prove useful in modulating dopamine activity in condi-
tions such as schizophrenia and provide dopaminergic tone in
Figure 2. Structures of dopaminergic drug candidates.
Figure 3. Structures of serotonergic drug candidates.
provided medicinal chemists with a solid starting point for their
design of innovative therapeutics (Figure 1).
Dopaminergic Drug Candidates
The dopamine hypothesis of schizophrenia has prompted vast
research in an attempt to achieve normalization of dopaminergic
activity. Studies have shown that neuroleptic therapy with
antipsychotic drugs with apparent specificity for the limbic as
opposed to the striatal region of the brain may provide efficacy
with a lower risk of extrapyramidal side effects (EPS).5,6 Our
early research efforts in this area focused on developing novel
atypical antipsychotic drugs that exhibited weak or moderate
antagonist activity at D2 receptors as well as 5-HT2 antagonist
activity.7 This work led to the design and discovery of two
atypical antipsychotic agents: gevotroline 1 and carvotroline 2.
Both compounds demonstrated profiles in animal models of
schizophrenia that suggested they might provide antipsychotic
efficacy with reduced liabilities. For example, 1 and 2 blocked
apomorphine-induced climbing in rats more potently than
apomorphine-induced stereotypy and both compounds inhibited
Figure 4. Major human metabolites of Effexor.

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Journal of Medicinal Chemistry, 2009, Vol. 52, No. 1
Award Address
Figure 5. High throughput screening of druglike properties.
Compound 8 represented the first-in-class of SNRIs. It
demonstrated efficacy in a broad range of patients including
those that were difficult to treat. Since its launch in 1997 as
Effexor XR, it has become the mainline therapy for major
depressive disorders (MDD) and has been shown to have higher
remission rates than SSRIs.25
The remarkable clinical efficacy of Effexor XR that has
benefited over 15-million patients since its launch has prompted
the search for a second generation SNRI. Consequently,
Duloxetine was launched in 2004 and is reported to have more
balanced affinities at the serotonin transporter (SERT) and
norepinephrine transporter (NET). We observed that 8 is
metabolized in the liver into three metabolites (Figure 4). One
major metabolite, O-desmethyl venlafaxine (ODV) 9 is more
bioavailable than Effexor and is also an inhibitor of both
serotonin and norepinephrine reuptake.26 Further investigation
resulted in its FDA approval and launch in 2008 as Pristiq.
Figure 6. Multidimensional lead optimization.
conditions where dopamine levels are low, such as in Parkin-
son’s disease. Compound 3 advanced to phase II (Figure 2).
Serotonergic Drug Candidates
The discovery of the aminotetralin 8-OH-DPAT, a potent
selective 5-HT1A full agonist, facilitated the development of
several 5-HT1A ligands.15 Our efforts in this area led to the
discovery of 5-HT1A partial agonist zalespirone 4 and mixed
5-HT1A/5-HT2 antagonist adatanserin 5; both demonstrated
anxiolytic activity in animal models and advanced to phase II
for the treatment of anxiety disorders.16-20
Building upon structural features of 4 and 5 led to the
discovery of a number of selective 5-HT1A antagonists,
including WAY-100,635 (6) and lecozotan (7).21 The lack of
intrinsic activity of 6 in multiple assay systems has made it a
widely used pharmacological tool, but its poor oral bioavail-
ability limited its clinical potential. Compound 7 was efficacious
orally in reversing cognitive deficits in monkeys and advanced
to phase II for the treatment of Alzheimer’s disease (Figure
3).22,23
Multitarget ligand-based designs have been successfully
utilized in the search for effective antidepressant drug candidates.
While the majority of antidepressant research in the 1980s
focused on design of novel selective serotonin reuptake inhibi-
tors (SSRIs), we focused our efforts on the design of multitarget
serotonin/norepinephrine reuptake inhibitors (SNRIs).
We capitalized on the existing structural similarities between
one of our earlier opiate analgesic leads, ciramidol, and
antidepressants that were under clinical investigation.24 Cira-
midol was further optimized (Scheme 1) by reducing its chiral
centers from three to one and incorporating an alkylamine
pharmacophore in a three-step synthesis to afford Effexor
(venlafaxine WY-45,030, 8).
Multidimensional Lead Optimization
Drug discovery has undergone considerable changes during
the past 2 decades as new enabling technologies have been
introduced. These have provided us with new opportunities to
increase drug discovery success and efficiencies on all levels.
These new technologies not only assist in the optimization of
biological properties of lead compounds but also allow the
chemist to address pharmaceutical parameters and druglike
physical properties earlier in the drug design process and on a
much larger scale than was previously possible. In the past,
selection and optimization of lead compounds and the selection
of drug candidates were driven primarily by results from
biological assays, but recently parallel druglike property opti-
mization has added a new discovery dimension.27-29
Pharmaceutical Profiling. Structure-Properties
Relationship (SPR)
Druglike compounds are defined as those that have suf-
ficiently acceptable chemicophysical and ADME properties and
sufficiently acceptable toxicity to survive through the completion
of human phase I clinical trials. Drug properties have always
been a prominent component of the development phase, where
detailed studies are performed on formulation, stability, PK,
metabolism, and toxicity. However, in recent years it is has
become imperative to integrate drug property evaluation into
the discovery process. This has been achieved by building

Award Address
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 1 5
Figure 7. Comparing the active sites of MMPs and TACE.
Scheme 2. Evolution of TMI-005
capability for measuring ensembles of essential “druglike
properties”. This structure-property relationship (SPR) informa-
tion complements traditional SAR information and is rapidly
becoming an essential tool for medicinal chemists. It allows
the chemist to address druglike properties earlier in the drug-
design process as well as providing information that can help
in the interpretation of results from in vitro and in vivo assays.
In many instances poor efficacy in in vivo models may be
due to low concentrations in the plasma and target tissues. This
low bioavailability can be caused by a number of physical
properties, such as poor solubility, poor permeability and
absorption, active transport, and low metabolic stability.30,31 In
particular, poor efficacy for CNS drug candidates in vivo may
be caused by poor penetration of the blood-brain barrier (BBB)
and/or low levels of free drug in the CNS. For CNS drug
discovery, often the goal is to optimize unbound drug brain/
plasma (B/P) ratios rather than total B/P ratios or total brain
drug concentration.32
High throughput assays for physicochemical properties,
solubility, permeability, lipophilicity, stability, and Pka-in vitro
ADME (metabolism, transporters, protein binding, and CYP
inhibition) and in vivo PK exposure, provided a wealth of data
for the discovery scientists to make informed decisions (Figure
5). These assays complement the in silico approaches currently
utilized to predict physicochemical parameters of molecules such
as MetaSite.
safety profiles and finding the suitable formulation for initiating
first-in-human trials (Figure 6).
Structure-Based Design
Rational drug design involves the use of three-dimensional
information resulting from interactions of small molecules with
biomolecules utilizing techniques such as X-ray crystallography
and NMR spectroscopy. This approach has been successfully
utilized in the discovery of several drug candidates, particularly
the design of enzyme inhibitors.33 In an effort to find effective
therapies for treatment of inflammatory diseases, inhibition of
TNF-R converting enzyme (TACE) represented an attractive
drug discovery target for reducing the circulating level of the
proinflammatory soluble protein TNF-R. Sulfonamide hydrox-
amate TACE inhibitor leads were further optimized for potency
and selectivity over matrix metalloproteases (MMPs) utilizing
information derived from X-ray cocrystal structures. The S1′
pocket of TACE consists of an initial region resembling the
shallow S1′ pocket of MMP-1 in size and depth. The rest of
the TACE S1′ is no longer extended linearly as in MMP-9 and
MMP-13; rather, the extended channel is almost perpendicular
to the S1′ pocket, directed toward the S3′ surface (Figure 7).34
Given this information and by use of a solid phase combi-
natorial chemistry approach, a series of phenoxyacetylene
hydroxamates was synthesized. Optimizing these leads for
potency and selectivity helped define the SAR requirements for
the TACE binding site.35 Subsequent optimization for PK and
in vivo efficacy through parallel synthesis led to the discovery
of TMI-005 10, a propargylic hydroxylhydroxyamic acid that
Multidimensional optimization combining the physicochem-
ical properties data with biological activity at the target site
added tremendous value to the selection of development track
candidates. The process is further guided by favorable PK and

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Journal of Medicinal Chemistry, 2009, Vol. 52, No. 1
Award Address
Figure 8. Binding of rapamycin to FKBP and mTOR42.
Scheme 3. Functionalization of C-42 Alcohol Led to the Discovery of Torisel
advanced to phase II for treatment of rheumatoid arthritis
(Scheme 2).36
Natural-product-based drug discovery was successfully ap-
plied to rapamycin 11, a novel immunosuppressant natural
product with a unique mechanism.40 It binds to the effector
protein FKBP and forms a complex that binds to another effector
protein, m-TOR41 (mammalian target of rapamycin, Figure 8).
Rapamycin was marketed in 1999 as Rapamune for treatment
of transplantation rejection.
Natural-Product-Based Drug Design
Natural products and their derivatives have historically been
invaluable as a source of innovative therapeutics. Natural-
products-based drug discovery reached its peak during the 1970s
and 1980s. Of the small molecule NCEs introduced to the
market between 1981 and 2002, roughly half (49%) were natural
products, semisynthetic natural product derivatives, or synthetic
compounds based on natural product pharmacology.37,38
Despite this success, pharmaceutical research into natural
products has encountered significant challenges during the past
decade. In recent years, the pharmaceutical industry has placed
low emphasis on natural-product-based drug discovery and
several big pharma companies have exited natural product
research. The decline in natural product research could be
attributed to several factors such as lack of compatibility of
traditional natural product extract libraries with HTS, demand
on reducing hit-to-lead cycle time which favors screening of
small molecule chemical libraries, waning interest in infectious
disease research which is usually benefited from screening of
natural products, development of combinatorial chemistry, and
challenges in gaining access to biodiversity.
We embarked on a non-HTS approach looking at our
rapamycin equity in order to expand its therapeutic utility.
Applying a semisynthetic strategy to the C-42 secondary alcohol
functionality led to the discovery of CCI-779 12, a cell cycle
inhibitor with potent antitumor activity that was marketed in
2007 as Torisel for treatment of renal cell carcinoma43 (Scheme
3).
The discovery of Torisel will be the subject of an upcoming
case study perspective article.
It is well established that immunophilins ligands such as FK-
506 demonstrate neuroprotective activity in animal ischemia
models. A key event in this process was thought to be binding
to FKBP-12, which can trigger a cascade of events, although
the exact mechanism is not fully known.44,45 One hindering
factor to using these compounds as neuroprotectants has been
their immunosuppressant activity. However, it is possible to
achieve neuroprotection using immunophilins without immu-
nosupression.46-48 Efforts aimed at exploring the role of these
nonimmunosuppresive immunophilin ligands in neuroprotection
revealed that, while binding to FKBP-12 was still a key step,
formation of a ternary complex with calcineurin may not be
responsible for mediating neuroprotection and neuroregenera-
tion.
Advances in technology have enabled natural-product-based
drug discovery to operate on a more rational basis, and this has
spurred renewed interest in natural products research which is
now feasible using precise synthetic methods and high-resolution
analytical tools.39 Genetic engineering of biosynthetic pathways
of biologically active natural product scaffolds can provide new
starting points for optimization of these privileged structures.

Award Address
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 1 7
Scheme 4. Synthesis of ILS-920 (13)
Our efforts in designing non-immunosupressant neuropro-
tectant immunophilins focused on the pharmacophore that binds
to the m-TOR effector protein. Structural manipulation targeting
the C1-C4 triene of rapamycin utilizing Diels-Alder chemistry
with a variety of dienophiles led to the synthesis of novel
nonimmunosuppressant neuroprotective rapamycin derivatives.
One of these, the semisynthetic adduct ILS-920 13, lacked
immunosuppressant properties and demonstrated good brain
penetration. It was synthesized in a three-step synthesis by
reacting rapamycin with nitrosobenzene followed by hydrogena-
tion of the six-membered cyclic adduct (Scheme 4).
in sensorimotor performance compared to placebo lasted up to
3 months. Taken together, these data suggest that ILS-920 not
only functions as a neuroprotectant but also promotes functional
recovery. These exciting results will be featured in an upcoming
manuscript.
Graziani et al. have provided evidence that that the neuro-
protective and neuroregenerative activities of 13 may involve
binding to the effector protein, FKBP-52. In addition, inhibition
of L-type calcium channel currents may contribute to the
compound’s neuroprotective activity.50
Compound 13 promoted survival of E16 primary rat cortical
neurons in culture and stimulated neurite outgrowth in that
system (Figure 9).49 The compound demonstrated neuroprotec-
tion in a rat transient mCAO focal ischemia model in a dose-
dependent manner (Figure 10).49 In that model, animals treated
with 13 showed reduced neurological deficits compared with
placebo-treated animals, as measured by sensorimotor perfor-
mance. In a permanent focal ischemia model, that improvement
Closing Remarks and Future Outlook
During my 26-year journey working in the pharmaceutical
industry, I have experienced vast changes in medicinal chemistry
approaches where new NCE drug candidates were discovered.
Shifting emphasis from optimizing biology of synthesized
molecules into optimizing druglike properties and the ADMET
profile led to reduction in attrition rate of compounds in
development. Current and future approaches include nontradi-
tional approaches to the discovery of drug candidates. This will
include bridging the gap between small-molecule and protein
drug candidates by applying multiplatforms (small molecules,
vaccines, and proteins) in an integrated strategy to tackle a given
disease target. We have adopted this approach in applying our
research capabilities to improve upon current approaches to AD
treatment by utilizing multiple research platforms.
In addition to developing drugs that more effectively control
AD symptoms, we are expending significant resources on novel
approaches to slow or halt the progression of the disease. We are
using three technology platforms in our AD development efforts.
Figure 9. Neuroprotective/neuroregenerative activity of compound 13
on E16 primary rat neurons in culture: (a) effect of 13 on neuronal
survival; (b) compound 13 promoting neurite outgrowth.
Figure 10. Compound 13 reduces infarct volume in a rat transient
mCAO model.

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Journal of Medicinal Chemistry, 2009, Vol. 52, No. 1
Award Address
Biography
Our small molecule approach involves designing γ-secretase and
BACE inhibitors to inhibit formation of ꢀ-amyloid protein (Aꢀ).
We have also taken a biopharmaceutical approach that involves
designing recombinant proteins, vaccines, and human recombinant
antibodies that stimulate the body to clear both soluble Aꢀ and
deposited ꢀ-amyloid (plaque) from the brain.
Nontraditional approaches to natural-products-based drug
discovery are now being adopted such as the use of fractionated
libraries which result in broader assay compatibility and fewer
interferences and lead to faster identification and isolation of
active leads. Future natural products drug discovery leads not
only will capitalize on semisynthetic approaches but will focus
on a “customized natural products approach” wherein new lead
molecules once thought to be inaccessible by semisynthesis are
generated through biosynthesis and genetic engineering. We
successfully adopted both strategies that resulted in the discovery
of the anticancer drug Torisel, neuroprotectant drug candidate
ILS-920, and several new natural products derivatives currently
in development.
Magid Abou-Gharbia received his B.Sc. (1971) and M.Sc
(1974) degrees from Cairo University in Pharmacy and Pharma-
ceutical Sciences and his Ph.D. in Organic Chemistry from the
University of Pennsylvania (1979) under the direction of Professor
Madeleine Joullie. After an NIH postdoctoral fellowship at the
Medical School and Chemistry Department at Temple University
he joined Wyeth in 1982. He spent 26 years working in many
therapeutic areas where he and his research team have made
numerous contributions in medicinal chemistry that resulted in the
discovery of several innovative marketed drugs, few of which are
described in this article. In September 2008 he joined the School
of Pharmacy at Temple University as Professor of Medicinal
Chemistry and director of the Center for Drug Discovery Research
(CDDR).
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sands in HTS). Compounds screened are usually of smaller
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As more innovative new drugs acting at novel targets advance
through development, it becomes increasingly important to
establish a correlation between preclinical efficacy in animal
models and efficacy in humans. Translational medicine is rapidly
emerging in many biomedical research institutions as a tool to
bridge this gap between preclinical and clinical studies, often
referred to as “from bench to patient bedside”. Medicinal
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Thus, while drug discovery hurdles remain many and high,
the future holds a great promise for this industry. We will
continue discovering major breakthrough therapies that will
address many unmet medical needs, such as disease-halting
drugs for the treatment of Alzheimer’s disease, drugs to eradicate
AIDS, and drugs to attack resistant cancers, treat strokes, MS,
and other debilitating diseases.
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Acknowledgment. The author is indebted to many Wyeth
researchers who are responsible for the discovery of these many
breakthroughs and first-in-class drug candidates. Sincere thanks go
to my colleague Wayne Childers not only for providing constructive
feedback and suggestions to the content of the presentation and
this article but also for his dedicated tireless efforts in medicinal
chemistry during the past 20 years. I also express my deep
appreciation and thanks to Cynthia Tagliaferi for her efforts in
preparing this manuscript.
(19) Abou-Gharbia, M.; Moyer, J. WY-50,324, anxiolytic/antidepressant.
Drugs Future 1990, 15 (11), 1093.

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(20) Abou-Gharbia, M.; Childers, W.; Fletcher, H., Jr.; McGaughey, G.;
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