Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 6, Number 5, 2006
Contents
Successful Drug Discovery: Rules and Examples
Guest Editor: Dr. David C. Swinney
Editorial Pp. 403-404
Discovery and Clinical Development of Dutasteride, a Potent
Dual 5 α-Reductase
Inhibitor Pp. 405-421
Stephen V. Frye
[Abstract]
Optimization of Small Molecule Drugs Binding to Highly
Polar Target Sites: Lessons from the Discovery and Development
of Neuraminidase Inhibitors Pp. 423-434
Klaus Klumpp and Bradford J. Graves
[Abstract]
Lessons from the Drug Discovery of Lapatinib, a Dual
ErbB1/2 Tyrosine Kinase Inhibitor Pp. 435-460
Karen E. Lackey
[Abstract]
Biochemical Mechanisms of New Molecular Entities (NMEs)
Approved by United States FDA During 2001-2004: Mechanisms
Leading to Optimal Efficacy and Safety Pp.
461-478
David C. Swinney
[Abstract]
Malaria and Other Diseases of the Developing World
A Medicinal Chemistry Perspective on 4-Aminoquinoline
Antimalarial Drugs Pp. 479-507
Paul M. O’ Neill, Stephen A. Ward, Neil
Berry, J. Prince Jeyadevan, Giancarlo Biagini, Egbaleh Asadollaly,
B. Kevin Park and Patrick G. Bray
[Abstract]
From Artemisinin to New Artemisinin Antimalarials:
Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry
and Medicinal Chemistry Requirements Pp. 509-537
Richard K. Haynes
[Abstract]
Mechanisms of Drug Action and Drug Resistance
in Leishmania as Basis for Therapeutic Target Identification
and Design of Antileishmanial Modulators Pp. 539-550
Philippe M. Loiseau and Christian Bories
[Abstract]
Abstracts
[Back to top]
Editorial
A fundamental issue plaguing drug discovery is the high failure
rate. Funding of the failed research is a contributor to the
high cost of medicines and consequently, the rising cost of
health care. How can the failure rate of drug discovery be
minimized and the success rate of drug discovery increased?
This issue of Current Topics in Medicinal Chemistry
takes aim at learning what it takes for success from successful
drug discovery. Three case studies and a review article provide
insights into the process of successful drug discovery.
What factors are important for drug discovery success? Two
eminent drug discovers, Dr. Paul Janssen and Sir James Black,
both found that a clear concept or idea, a good chemical starting
point, time to allow iterative evolution, intense concentration
and relentless commitment were the keys to success [1,2].
They believed that lack of commitment and technology driven
projects are contributors to failure. The success stories
in this issue describe the ideas that initiated the projects,
the chemical starting points and the iterative processes used
to identify the new medicines. Steven Frye of GSK chronicles
the successful path to the discovery of the dual 5α
reductase inhibitor dutasteride. He explains the origination
of the idea for a once daily dual 5α-reductase
inhibitor, the chemical starting point from steroid substrate
analogs and past experience with finasteride, and the use
of dog as an iterative model to optimize pharmacokinetics.
The knowledge gained from experience with finasteride, the
first 5α-reductase
inhibitor, was used to hypothesize that a dual acting mechanism-based
inhibitor is required to achieve greater clinical suppression
of dihydrotestosterone and clinical efficacy against benign
prostatic hyperplasia. The efforts of the GSK scientists eventually
proved the hypothesis correct. Klaus Klumpp and Bradford Graves
of Roche describe the discovery of the orally active influenza
neuraminidase inhibitor, Tamiflu. Previous influenza neuraminidase
inhibitors had high affinity but poor pharmacokinetic properties
because of the polar charged character of the binding site.
The idea was to find a molecule with less polarity and that
still retained the activity. Starting with transition state
mimics, they found a subtle conformational change in the active
site that exposed a non-polar surface allowing a molecule
to have both high binding affinity and drug-like properties.
Karen Lackey of GSK recounts the path to discovery of Lapatinib,
a dual EGF receptor/ErbB-2 kinase inhibitor currently in phase
III studies for cancer. She points out that the idea was to
target the two receptors with quinazoline-like compounds.
She emphasizes how increased knowledge about the target and
chemical series assisted the evolution of the efficacy and
mechanism of action assays. A key breakthrough for their work
was the discovery of molecules with cellular potency against
both isoforms of the EGF receptor. A mathematical index is
described which was used to formulate the medicinal chemistry
plan. Retrospectively, it was found that these molecules had
a unique binding mode to the kinase. These three successful
drug discovery examples all have in common a clear idea of
what they wished to achieve, good chemical starting points
and evolved iterative processes to optimize the drug candidates.
Janssen and Black identified the time required for iteration
as a potential barrier to success [1,2]. A more rapid iteration
may occur when experience from past drug discovery success
can be used to guide current research. Past experience can
also help define when a compound is sufficiently optimized
(when there have been sufficient iterations). A review of
the biochemical mechanism of action of new molecular entities
approved by the US FDA between 2001 and 2004 suggests that
the mechanism of drug action will contribute to a drug’s
therapeutic index. The potential for mechanism-based toxicity
was identified as a key determinant of a drug’s mechanism
of action. Binding mechanisms will evolve for targets with
no mechanism-based toxicity that maximize the effect at the
lowest drug concentration by avoiding mass action competition
to minimize off-target toxicities, whereas drugs with a potential
for mechanism-based toxicity require a mechanism to minimize
toxicity while retaining efficacy. Targeting drug targets
that have mechanism-based toxicity has a greater risk requiring
early iterative optimization of both efficacy and toxicity.
Awareness of rules based on past drug discovery experience
should facilitate drug discovery by decreasing the time required
for the iterative evolution of molecules with the characteristics
to be a medicine.
Why is the failure rate so high? The overall formula for success,
as described by Janssen and Black and supported by the case
studies described here, does not seem that difficult. Begin
with a good idea or concept, a good chemical starting point,
and utilize the appropriate technologies to iteratively evolve
the new medicine. Of course, this does require time and commitment
to allow the evolution to occur. Potential pitfalls leading
to failure may occur at all stages. An over reliance on qualitative
or poor quality data may contaminate ideas and lead to poor
decisions. Many new off the shelf technologies are now available
that can be run by persons not skilled in the use of the technologies.
This may lead to poor data and bad decisions. Another pitfall
relates to a good chemical starting point. Janssen and Black
pointed out that they always had good chemical starting points.
However in the age of new targets from the human genome there
are not always good chemical starting points. Good chemical
starting points may be identified using the many new lead
discovery technologies, however this takes time. Once a lead
is identified the clock has usually been ticking on a program
for a couple of years and the sponsors may not have the patience
to invest the time and money required to further optimize
the new lead into a medicine. Another potential pitfall is
the iteration process itself. New technologies are in place
to make it faster and cheaper. However are they optimizing
for the correct properties? Is sufficient time invested to
ensure that the assays themselves are properly optimized?
Another reason for the limited success of current drug discovery
is that often current drug discovery is technique driven and
not idea driven. There can be a tendency to try and force
a ‘square peg in a round hole’. This tendency
is driven by demand for shorten time lines, a desperate need
to fill productivity quotas and aided by improper use of the
ever expanding tools available to drug discovers. Patience
and rules based on previous experiences may help to minimize
the tendency to try a force a ‘square peg in a round
hole’.
Successful drug discovery is a long endeavor requiring a good
idea, a good chemical starting point, time, rules and technologies
to allow iterative evolution of the new medicine and, perhaps
most importantly, a scientific champion who will obstinately
find ways to face each challenge. This is the individual with
the idea, persistence and patience to find the ‘round
peg for the round hole’.
The path to successful drug discovery may be considered analogous
to finding the solution to a mathematical equation. You need
a good starting point, computing power and time to do the
multiple iterations required to find the minima and rules
based on experience to ensure that the solution is the global
minima, not a local minima.
1. Black, J. Personal perspective on Dr. Paul Janssen. J.
Med. Chem. 2005, 48, 1687-1688.
2. Interview with Sir James Black. Mol. Interv. 2004,
4, 139-142.
Dr. David C. Swinney
Biochemical Pharmacology
Roche Palo Alto
Palo Alto, CA
USA
[Back to top]
Discovery and Clinical Development of Dutasteride,
a Potent Dual 5
α-Reductase Inhibitor
Stephen V. Frye
In this review the preclinical medicinal chemistry, biochemistry
and clinical results achieved in the treatment of prostatic
disease with dutasteride, a dual inhibitor of type 1 and type
2 5α-reductase
are described. During the discovery phase, dutasteride was
optimized to inhibit both forms of human 5α-reductase
(5AR) via extensive structure activity relationship
studies versus the cloned human isozymes. Dutasteride has
subsequently been shown to improve disease measures in patients
with symptomatic benign prostatic hyperplasia (BPH) in three
randomized, placebo-controlled, Phase III clinical studies
lasting for 2 years. Additionally, dutasteride is now under
study for the ability to reduce the incidence of prostate
cancer in men at high risk of the disease – an indication
where the unique dual inhibitor nature, half-life and tolerability
of dutasteride may be especially significant factors in determining
treatment success. The connections between preclinical drug
design and clinical outcomes during the discovery and development
of dutasteride are exemplified.
[Back to top]
Optimization of Small Molecule Drugs Binding to Highly
Polar Target Sites: Lessons from the Discovery and Development
of Neuraminidase Inhibitors
Klaus Klumpp and Bradford J. Graves
Binding affinity optimization of small molecules
interacting with polar binding sites on target proteins is
a formidable, but not uncommon challenge in drug discovery.
The challenge relates to the difficulty of integrating favourable
and unfavourable polar, non-polar and conformation contributions
into overall favourable binding energies. This review describes
the surprising breakthrough findings leading to the development
of Tamiflu, a clinically efficacious orally bioavailable drug
targeting the active site of influenza neuraminidase (NA).
The NA active site is highly polar and formed mostly by arginine,
aspartate and glutamate residues. This active site structure
evolved for efficient interaction with charged sialic acid
moieties on glycoproteins and stabilization of an oxocarbonium
ion in the transition state of the neuraminidase reaction.
The initial strategy of optimizing polar interactions in transition
state analogs led to NA inhibitors (NAIs) with sub-nanomolar
binding affinities, but such compounds were highly polar and
lacked oral bioavailability. The realization of the possibility
to achieve high affinity binding in a highly polar active
site through optimization of non-polar and van-der-Waals interactions
initially appeared counterintuitive and required a few serendipitous
findings, but was key to reduce the polarity of drug candidates,
avoid large desolvation penalties and achieve oral bioavailability.
[Back to top]
Lessons from the Drug Discovery of Lapatinib, a Dual
ErbB1/2 Tyrosine Kinase Inhibitor
Karen E. Lackey
Protein Kinases offer many opportunities
for drug intervention points since phosphorylation is the
most common post-translational modification [1]. Phosphorylation
regulates activity, location, degradation, conformation and
the aberrant activity is implicated in many diseases, including
cancer, inflammation, cardiovascular and central nervous system
diseases [2-5]. The focus of this review will be on the generation
of highly effective signaling inhibitors targeting members
of the erbB family of receptor tyrosine kinases, EGFR and
ErbB-2, also known as transmembrane Type 1 receptor tyrosine
kinases of the HER family of receptors. Ligand binding to
the receptor causes a conformational change which activates
the tyrosine kinase domain leading to autophosphorylation.
This autophosphorylation activates the RAS/mitogen activated
protein (MAP) kinase and phosphoinositol-3-kinase (PI3K) pathways
leading to a myriad of signaling and cellular activities [6].
Type 1 receptors are over-expressed in a variety of cancers
and generally correlate with poor prognosis. For this reason,
scientists at GlaxoSmithKline and many others in the scientific
community, target the ATP binding site of the intracellular
portion of the protein to block the aberrant signaling event.
This review intends to cover the lessons learned in the discovery
of lapatinib (GW572016, GW2016) by pulling together the various
different publications that have been generated in distinct
disciplines on aspects of the drug discovery program. Data
analyses and correlation of assay data to help with the design
of drug like molecules will be included and will demonstrate
a break from the traditional focus on absolute potency as
a guiding factor in lead compound selection.
[Back to top]
Biochemical Mechanisms of New Molecular Entities (NMEs)
Approved by United States FDA During 2001-2004: Mechanisms
Leading to Optimal Efficacy and Safety
David C. Swinney
The United States FDA approved 85 New Molecular Entities
(NMEs) during the period from January 2001 to November 2004
of which 60 were pharmaceuticals with known molecular targets.
The majority targeted enzymes (48%) or G-protein coupled receptors
(GPCRs) (33%). Eighty percent of the NMEs interacted at the
same site as endogenous effector; either as competitive inhibitor/antagonist
(67%) or agonist (13%). Three biochemical operations defined
the modes of action of the NMEs: 1) mass action competition
(equilibrium), 2) a drug stabilized conformational change
in the target that is important to the response (conformational)
and/or 3) drug action is less-responsive to mass action competition
with effectors due to non-equilibrium kinetics (non-equilibrium
kinetic). Approximately 80% of the NMEs elicit a response
utilizing conformational and/or non-equilibrium kinetic mechanisms.
The remaining 20% of NMEs find mass action competition with
the endogenous substrate or ligand sufficient for therapeutic
utility. These observations indicate that for the majority
of drug targets, mass action driven equilibrium binding alone
may not be sufficient for maximal therapeutic utility. A key
determinant of the biochemical mode of action for these NMEs
was to minimize the potential for toxicity, either by providing
a maximal response at a low dose to minimize off-target toxicities,
or by providing a mechanism to minimize the incidence of mechanism-based
toxicity while retaining a sufficiently efficacious response.
This principle appears to be independent of target class and
provides insight as to intrinsic biochemical features and
approaches required for a maximal therapeutic index.
[Back to top]
A Medicinal Chemistry Perspective on 4-Aminoquinoline
Antimalarial Drugs
Paul M. O’ Neill, Stephen A. Ward, Neil
Berry, J. Prince Jeyadevan, Giancarlo Biagini, Egbaleh Asadollaly,
B. Kevin Park and Patrick G. Bray
A broad overview is presented describing the current knowledge
and the ongoing research concerning the 4-aminoquinolines
(4AQ) as chemotherapeutic antimalarial agents. Included are
discussions of mechanism of action, structure activity relationships
(SAR), chemistry, metabolism and toxicity and parasite resistance
mechanisms. In discussions of SAR, particular emphasis has
been given to activity versus chloroquine resistant strains
of Plasmodium falciparum. Promising new
lead compounds undergoing development are described and an
overview of physicochemical properties of chloroquine and
amodiaquine analogues is also included.
[Back to top]
From Artemisinin to New Artemisinin Antimalarials:
Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry
and Medicinal Chemistry Requirements
Richard K. Haynes
The artemisinin derivatives, dihydroartemisinin (DHA), artesunate,
atemether and arteether, are currently used for treatment
of malaria in artemisinin combination therapies (ACT) with
longer half-life drugs. The demand is enormous - in 2005,
the estimated global demand for one such ACT alone, artemether-lumifantrine,
which constitutes about 70% of all current clinically-used
ACTs, is for 120 million adult treatment courses. At 0.5 gm
of artemether per total dose regimen, the amount of artemisinin
required is approximately 114 tons. This has placed substantial
stress on total artemisinin supplies world-wide, and considerable
attention is being focussed on enhancing availability of artemisinin
by improvement in horticultural practice and extraction of
artemisinin from Artemisia annua. Artemisinic acid,
which also occurs in A. annua, can be converted into
artemisinin and is the ultimate target of a biotechnological
approach, which if successful, will augment artemisinin supply
in the future. The conversion of artemisinin into the known
artemisinin derivatives, and problems with the methods are
critically reviewed. Some attention is paid to mechanistic
aspects which clarify stereochemistry. The current artemisinins
are by no means ideal drugs. Artesunate in particular is incompatible
with basic quinolines by virtue of proton transfer, and has
intrinsic chemical instability. At pH 1.2, conversion to DHA
is rapid, with t½
26 min, and at pH 7.4, t½
is about 10 hours. With a pKa
of 4.6, over 99% of artesunate will be ionized at pH 7.4,
and thus uptake by passive diffusion from the intestinal tract
will be minimal. Although a considerable effort has been vested
in the search for new artemisinins, largely through functionalization
of artemisinin at C-10, O-11 or at C-15 via artemisitene,
or of DHA at C-10, deliberate enhancement of the 'druggability'
of artemisinins by reducing lipophilicity, which at the same
time will attenuate the neurotoxicity characteristic of the
current derivatives, and enhance absorption, by and large
has not been considered. A review of the various types of
newer derivatives is given together with a consideration of
medicinal chemistry aspects.
[Back to top]
Mechanisms of Drug Action and Drug Resistance in Leishmania
as Basis for Therapeutic Target Identification and Design
of Antileishmanial Modulators
Philippe M. Loiseau and Christian Bories
The control of Leishmania infections relies
primarily on chemotherapy. The arsenal of drugs available
against Leishmania infections is limited and includes
pentavalent antimonials, pentamidine, amphotericin B, miltefosine,
paromomycin, allopurinol, and few other drugs at various stages
of their development process. Knowledge about action and resistance
mechanisms involved may allow the development of new drugs
that minimise or circumvent drug resistance or may identify
new targets for drug development. The aim of this review is
to propose some chemical topics to design new modulators from
the mechanisms of action of drugs and resistance mechanisms
to drugs used in the clinic against Leishmania infections.
Thus, different classes of ABC transporters extrude antimonials
in Leishmania resulting in drug-resistant phenotypes.
Compounds interfering with thiol and polyamine metabolism
could be designed to inhibit the antimonial detoxication and
therefore, such compounds could be used in combination with
antimonials. New diamidines could be synthesized in regard
to their ability to inhibit topoisomerase II. The challenge
for amphotericin B is to be absorbed by oral route requiring
labile physico-chemical modifications. New sesquiterpens and
flavonoids have to be developed as reversant of antimonial
resistance. Although some studies have focused on developing
inhibitors against these resistant phenotypes, new efficient
modulators that are able to inhibit drug efflux are needed.
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