Dr. P. Wipf Page 1 of 42 2/14/2008 Pharm 5119 - Medicinal ...
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Pharm 5119 - Medicinal Chemistry & Drug Discovery Dr. Peter Wipf Department of Chemistry University of Pittsburgh http://ccc.chem.pitt.edu/wipf/index.html University of Pittsburgh Center for Chemical Methodologies & Library Development Dr. P. Wipf Page 1 of 42 2/14/2008
Transcript of Dr. P. Wipf Page 1 of 42 2/14/2008 Pharm 5119 - Medicinal ...
Pharm 5119 - Medicinal Chemistry& Drug Discovery
Dr. Peter WipfDepartment of ChemistryUniversity of Pittsburgh
http://ccc.chem.pitt.edu/wipf/index.html
University of Pittsburgh Center for Chemical Methodologies & Library Development
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http://ccc.chem.pitt.edu/wipf/Courses.html
• Introduction • Survey of current drug targets • Drug discovery challenges • Methods to identify new leads • Case studies from industry • Structure-based design
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Medicinal ChemistryThe science that deals with the discovery or designof new therapeutic agents and their developmentinto useful medicines.
It involves:
• Organic Synthesis
• Biological Target Identification & AssayDevelopment
• Structure-Activity Relationships (SAR)
• Absorption, distribution, metabolism, andexcretion (ADME)
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0
20
40
60
80
100Ab
sorb
ance
Plate #
Drug Discovery Checkpoints
Target Identification1 gggcgtggag gagcccaccg accggagacc atttggggcc tggagatgcc atcggagggc61 aggagctcat cctggagagg ccaccgtaag gcctgacctg ggcctgggga gcttggcttg121 aggaagctnt gggccgacca aggccgccag gagatgggt
Target Characterization
Lead Definition
Lead Optimization
Candidate EvaluationDrug Formulation
Clinical Testing
1-2 y2-6 y
7 y
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Gene-Family Distribution of Current Drugs
Paolini, G. V.; Shapland, R. H. B.; van Hoorn, W. P.;Mason, J. S.; Hopkins, A. L., "Global mapping ofpharmacological space." Nature Biotechnology 2006, 24,805-815.
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Drug Potencies
Median affinity = 20 nM
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Rate of Target Innovation
High Target Innovation
Re-Use of EstablishedMechanisms
• Ca. 130 “privileged druggable domains” cover all current drug targets (vs. total number ofprotein families (16,000) and folds (10,000).• Of ca. 1,620 distinct human protein sequences are linked to a genetic disease, only 105 areactual drug targets.• Target innovation is slow - The average rate over the past 20 years has been quite constantat 5 new “drugged” targets per year.• The first approved indications for drugs acting on new targets are usually orphan diseases.
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What do Drugs have in common?
O
NH
N N
SS
O
O
NH2
O
O
NH
O
N
OOH
O
NH
OH
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‘Drug-like’ & ‘Lead-like’ Properties• Lipinski’s rule-of-five deals with orally active compounds that achieved phase II, soit is not a method to distinguish between drugs and non-drugs but point tocompounds that might have poor absorption or permeability.• A more general approach is to use rules based on limits of physicochemicalproperties and on structural filtering, in a progressive scoring function.• The evaluation for drug-like properties is based on:
Lipinski, C. A.; Lombardo, F.; Dominya, B. W.; Feeney, P. J., "Experimental and computational approaches to estimatesolubility and permeability in drug discovery and development settings." Adv. Drug Del. Rev. 1997, 23, 3-25.
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‘Drug-like’ & ‘Lead-like’ Properties• Optimization of a lead compound generally results in an increase of MW, log P,and complexity.• A lead-like filter needs to select polar compounds with simple chemical structures.• Hann, M. M.; Oprea, T. I. Curr. Op. Chem. Biol. 2004, 8, 255.• The evaluation for lead-like properties is based on:
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‘Drug-like’ & ‘Lead-like’ Properties• Reactive functionalities should be filtered:
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This compound was identified as a hit in an HTS screen - would you select it as alead structure?
N
S
N
NN
S
N
N
N
N
F3C
CF3
Cl
Cl
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A majority of medicinal chemists would also reject these structures (out of a list of2000). However, overall the consistency is low (ca. 25%; Lajiness, M. S.; Maggiora,G. M.; Shanmugasundaram, V., "Assessment of the Consistency of Medicinal Chemists inReviewing Sets of Compounds." J. Med. Chem. 2004, 47, 4891-4896)
C
O23
# timescompound
was rejected(out of 23)
N
N
OBr
22
OH
22
O
21
O P
O
O
PO
O
O
19
O
S
19
S
S SS
S
S
F
F
F
FF
F
O
SO
F
FF
O
19
N
O
O
18
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N N
HN
NH
N
O
O
N
F F
F F
F F
FF
18
NH
S
N
OO
OO
N
HN
S
18
N
S
H2N
N
O
N
N
18
O
N
O
OO
N
N
N
18
O
O
NO
O
ONO
O
17
O
O
17 SO O
N
NHO
S
O
OO
OH
17
Na+
O
O
17
NO
O
O
O
O
N
N
16
O
16
OH
O
15
N
N
N
N
15
Na+
O
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N
NN
N
N NN
NN
15
O S
S
O
O
O
O
O
O
Na+
Na+
15N
S OO
HNSS
O
O
N
O
O
S
O
O
O
Na+
15
N
NS
N
N S
NN
N N
F
F
FCl
Cl
F
FF
15
PN
N
NO
O
S
NH
N
N
S
15
N
P
N
O
N
NN
N
N
F 15
Cl
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Patents featuring “privileged” phenylpiperidines and related structures. Precedencein biological activity combined with ease of synthesis appear to be the main factorsin compound selection.
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“Big Pharma” Drug Discovery in the 21st CenturyThe Problem: The pharmaceutical industry is short of new drugs. In the 2nd part ofthe 20th century, about 50-60 new drugs (NCEs) were approved by the FDA everyyear. In contrast, in 2007, a historical low of 16 NCEs were approved (2000: 27;2001: 24; 2002: 18; 2003: 21; 2004: 36; 2005: 20; 2006: 18 NCEs;). Conversely,research costs for a new drug are estimated to be in the $1-1.5 Bi. range.Considering all high-profile failures in recent drug discovery, this figure is likely toincrease even further.
From: http://csdd.tufts.edu/InfoServices/OutlookReports.asp
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Current Drug Discovery Challenges
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Why Is Structural Diversity An Issue?
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Science 2007, 317, 1518.
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Fink, T.; Bruggesser, H.; Reymond, J.-L., "Virtualexploration of the small-molecule chemicaluniverse below 160 D." Angewandte Chemie,International Edition 2005, 44, 1504-1508.
And it has already started……
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In Search of New Leads…..
A lead can be characterized as a compound that• has some desirable biological activity,• is not extremely polar or lipophilic,• and does not contain toxic or reactive functional groups.Often, Lipinskiʼs rule of 5 (molecular weight (<500), lipophilicity (log P < 5,# of hydrogen bond donors <5, # of hydrogen bond acceptors <10), isused for evaluating the most obvious characteristics of a drug-like lead.The lead should also have a series of congeners that modulate biologicalactivity, indicating that further structural modification will improveselectivity and potency.
In order to maximize the success in finding new leads, it is important tohave access to structurally diverse libraries of small organic molecules.
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Leeson, P. D.; Davis, A. M.; Steele, J., "Drug-like properties: guiding principles for design - or chemicalprejudice?" Drug Discovery Today: Technologies 2004, 1, 189-195.
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Where Did (Do) Our Drugs Come From?
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Screening of natural product extracts
High-Pressure AcceleratedSolvent Extractor System
DCM & MeOHExtracts
Parallel HPLC
HT Solvent Concentrator
Multiwell PlatesFor HTS
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Examples of Natural Products as Leads & Drugs
Cardiac glycosides, morphine, quinine, salicylic acid, taxol,camptothecin, penicillin, cyclosporin A, warfarin, artemisine….
O
HO
RO
N
R = H: MorphineR = Me: Codeine
(pain killer)
HO
H H
OH
H
HO
H H
OH
HH
17-ethynylestradiol norethindrone
(the "Pill"; contraceptive)
Clarithromycin(antibacterial)
O
O
O
OH
OMeHO
O
O
O
OMe
OH
OHO
N
HOO N
S
O
NH2
CO2H
HH
Ampicillin(antibiotic)
N
O
O
OH
CO2H
Clavulanic acid(!-lactamase inhibitor)
Augmentin(antibiotic)
NN
O
O
O
N
HN
NNH
HN
N
O
O
O
OO
O
N
O
OH
N
O
NH
Cyclosporine A
1 2
3
4
567
89
1011
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Serendipitous Drug DiscoveryOne way to “discover” drugs
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Serendipitous Drug Discovery• The use of nitrous oxide and ether as narcotic gases in surgery resultedfrom the observation that people who inhaled these chemicals [in parties] didnot experience any pain after injury.• The vasodilatory activity of amyl nitrite and nitroglycerin was discovered bychemists who developed strong headaches after inhaling or ingesting minoramounts.• A wrong working hypothesis on chloral hydrate, which was supposed todegrade metabolically to narcotic chloroform, led to its application as a strongsedative (in reality, the metabolite trichloroethanol is the active form).Similarly, urethane was supposed to release ethanol but is a hypnotic byitself.• Acetylsalicylic acid was thought to be just a better tolerable prodrug ofsalicylic acid, but turned out to have a unique mechanism.• Phenolphthalein was considered as a useful dye for cheap wines; after aheroic self-experiment, a pharmacologist experienced its drastic diarrheicactivity.• Warfarin was used a rat poison.
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Serendipitous Discovery of Librium without a Lead
In 1955 Roche set out to prepare a series ofbenzheptoxadiazines as potential new tranquilizer drugs,but the actual structure was found to be that of aquinazoline 3-oxide.
2.4
N
O
N
R2
R1
X
Y
2.5
+-
N
N R1
O
R2
X
Y
In 1957, during a lab cleanup, a vial containing what was thought to bethe latter compound (X = 7-Cl, R1 = CH2NHCH3, R2 = C6H5) was sentfor testing, and it was highly active.
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Further analysis showed that the actual structure of the compound was the benzodiazepine 4-oxide, Librium, presumably produced in an unexpected reaction of the corresponding chloromethyl quinazoline 3-oxide with methylamine.
N
N CH2Cl
OCl
N
H
NNHCH3
OCl
CH2Cl
CH3NH2
N
CH2
NNHCH3
Cl
Cl
OH
N
N CH2NHCH3
OCl
..
-+
-+
-+
..
2.6
CH3NH2
N
N
Cl
NHCH3. HCl
O
chlordiazepoxide HCl2.3
+
-
Librium
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“Me Too” CompoundsCopying existing drugs with only minor chemical variations is usually referred to as “me too”research. Interestingly, sometimes these close analogs demonstrate major (usuallyunexpected) advantages, like the bioavailable, broad-spectrum lactamase-resistant penicillins,polar H1 antihistamines without sedative side effects, statins, or PDE5 inhibitors.
May & Baker Ltd. (1972)
Turko, I. V.; Ballard, S. A.; Francis,S. H.; Corbin, J. D., "Inhibition ofcyclic GMP-binding cyclic GMP-specific phosphodiesterase (type 5)by sildenafil and relatedcompounds." Mol. Pharmacol. 1999,56, 124-130.
Pfizer (1999) Pfizer (1992)
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The State-of-the-Art in Drug Discovery:
Small, incremental advances in fundamentalbiology, chemistry, and clinical sciences
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Southall, N. T.; Ajay, "Kinase Patent Space Visualization Using Chemical Replacements." J.Med. Chem. 2006, 49, 2103-2109.
N
N NH
N
OO
SO
ON
N
sildenafil (Pfizer)
N N NH
N
OO
SO
ON
N
vardenafil (Bayer)
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Examples of chemical replacements. A nitrogen was inserted into the scaffold of the other series; the starredatoms reflect connections back to the isomeric scaffolds. These examples cover 12 molecules from the chemicalseries of two patents granted to Sugen (Pfizer) and BMS. It would appear that BMS was influenced by Sugen..
A
* * HN *
*
B
HN
O
Br
HN
OHN
Br
HN
O
N
HN
OHN
N
HN
O
NH
HN
OHN
HN
O
O
B (continued)
HN
O
N
HN
O HN
N
HN
O
N
HN
O HN
N
O
O
HN
O
N
HN
O HN
N
O
O
Cl Cl
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Examples of analogs of AstraZeneca’s Iressa, obtained by chemical replacements.
HNN
HN
Cl
F
O
O
N
O
J&J
F
Cl
NH
N
N O
O
NH
S
O
O
F
Cl
NH
N
N O
O N
O
gefitinib (Iressa)
Cl
Cl
NH
N
N
O
O
Cl
NH
N
N
O
O
ClSugen
Pfizer
F
Cl
NH
N O
O N
O
Wyeth
N
Cl
F NH
N
N
NH
O
N O
Mitsubishi
BI
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Examples of the most frequent chemical replacements between different medicinal chemistrygroups.
Replacement Example #1 Example #2 Company #1:Company #2
N
N *
*
*
N *
*
*N
N
N
NH
O
O
N
NH
O
ON
AstraZeneca:Wyeth
N *
*
*N
N
N N
*
HN *
*
O
N
NH
O
ON
O
N N
N
NH
O
HN
O
O
O
Wyeth:Amgen
N
N *
*
*
N *
*
*N
N
N
NH
O
Br
N
NH
O
Br
N Pfizer:Wyeth
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Examples of the most frequent chemical replacements between different medicinal chemistrygroups.
Replacement Example #1 Example #2 Company #1:Company #2
N *
NH2
O *
N
NH
O
NO
HO
N
NH
O
O
HO
H2N
O
Wyeth:AstraZeneca
N
N **
N N
N **O
O
O
HN
N
NHN
O
O
O O
O
O
HN
N N
NHN
O
O
OCelltech:Amgen
O
O
*
HO N
*HO
O
OHO
N
HN
N
FN
N
HN N
HO
F
Aventis:Novartis
NN *
**
N*
**
Br
NH
NN
NNH
OH
Br
NH
N
NNH
OH
University:Pfizer
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Replacement Example #1 Example #2 Company #1:Company #2
*O
*
OHO
O
*
*NHO
HO
HN
ClO
NH
HN
ClOO
O
Pfizer:University
* * * NH*
HN
O
N
O
HN
O
NO
HNPfizer:Bristol-Myers Squibb
O
O
HN
*
*N
*
*
OH
FN
HN
N
NH2N
O
O
N
N
OH
N
NH2N
F Aventis:Merck
O
O
HN
*
*N
*
*
OH FN
HN
N
NH2N
O
ON
N
OH
N
NH2N
F Aventis:Merck
Examples of the most frequent chemical replacements between different medicinal chemistrygroups.
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Replacement Example #1 Example #2 Company #1:Company #2
*
O
OO
N
*
N
NH
NOO
NN
O
O
ONH
NOO
NN
NNH
N NH Vertex:Celltech
Examples of the most frequent chemical replacements between different medicinal chemistrygroups.
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An as of yet unknown analog of a potent, selective inhibitor of c-Src, constructedby applying one of the common chemical replacements to the lead structure.
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