Chemistry and Molecular Aspects of Drug Design and Action

380 Pages·2008·14.08 MB·English

by  E. A. Rekka

CHEMISTRY AND
MOLECULAR ASPECTS
OF
DRUG DESIGN
AND ACTION
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CHEMISTRY AND
MOLECULAR ASPECTS
OF
DRUG DESIGN
AND ACTION
E. A. Rekka
P. N. Kourounakis
Boca Raton London New York
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
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CRC Press
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International Standard Book Number‑13: 978‑0‑8493‑9006‑7 (Hardcover)
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Library of Congress Cataloging‑in‑Publication Data
Chemistry and molecular aspects of drug design and action / editors, E.A. Rekka
and P.N. Kourounakis.
p. ; cm.
“A CRC title.”
Includes bibliographical references and index.
ISBN‑13: 978‑0‑8493‑9006‑7 (hardcover : alk. paper)
ISBN‑10: 0‑8493‑9006‑0 (hardcover : alk. paper)
1. Pharmaceutical chemistry. 2. Drugs‑‑Design. I. Rekka, E. A. II.
Kourounakis, P. N. III. Title.
[DNLM: 1. Chemistry, Pharmaceutical. 2. Drug Design. 3. Pharmacologic
Actions. QV 744 C5173 2007]
RS403.C424 2007
615’.19‑‑dc22 2007010012
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
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Contents
Editors........................................................................................................................ix
Contributors...............................................................................................................xi
Rational.Drug.Design.Based.Mainly.on.the.Pathobiochemistry.of.the.Disease......xv
E. A. Rekka, A. P. Kourounakis, and P. N. Kourounakis
Part I
ChemICal, BIoChemICal, and BIologICal
asPeCts of PathoPhysIologICal CondItIons
Chapter 1 Inflammatory.Mechanisms.in.Alzheimer’s.Disease.and.Other.
Neurodegenerative.Disorders................................................................3
Joseph Rogers, Thomas Beach, Rena Li, Zhe Liang,
Lih-Fen Lue, Alexander Roher, Marwan Sabbagh, Yong Shen,
Ronald Strohmeyer, and Douglas Walker
Chapter 2 Treatment.Development.Strategies.for.Alzheimer’s.Disease..............13
Ernst Wülfert
Chapter 3 Lipoprotein-Associated.Phospholipase.A .as.A.New.Prognostic.
2
Factor.for.Coronary.Artery.Disease...................................................35
Alexandros D. Tselepis
Chapter 4 New.Molecular.Targets.for.the.Prevention.and.Treatment.of.
Gastrointestinal.Ulcers.and.Inflammation..........................................43
Sandor Szabo, Ganna Tolstanova, Lajos Nagy,
Longchuan Chen, Tetyana Khomenko, Xiaoming Deng, and
Zsuzsanna Sandor
Chapter 5 Stress.Activates.Corticotropin.Releasing:.Factor.Signaling.
Pathways:.Implication.in.Functional.Bowel.Disorders.......................75
Yvette Taché

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i Chemistry and Molecular Aspects of Drug Design and Action
Part II
ClassICal medICInal ChemIstry
Chapter 6 Design,.Synthesis,.and.Pharmacological.Evaluation.of..
High-Affinity.and.Selectivity.Sigma-1.and.Sigma-2.Receptor..
Ligands....................................................................................................93
Jacques H. Poupaert
Chapter 7 Synthesis.of.Biologically.Active.Taxoids..........................................101
K. C. Nicolaou and R. K. Guy
Chapter 8 From.the.Molecular.Pharmacology.to.the.Medicinal.Chemistry.
of.Cannabinoids................................................................................109
Didier M. Lambert
Chapter 9 An.Appraisal.of.Fomocaines:.Current.Situation.and.Outlook..........123
Herbert Oelschläger and Andreas Seeling
Chapter 10 Ligands.for.the.GABA.Recognition.Site.at.the.GABA .
A
Receptor:.Structure–Activity.Studies...............................................139
Bente Frølund, Uffe Kristiansen, Povl Krogsgaard-Larsen,
and Tommy Liljefors
Chapter 11 Strategies.for.Development.of.New.Lead.Structures.for.
Inhibition.of.Acetylcholinesterase....................................................149
Petra Kapkova, Vildan Alptuzun, Eberhard Heller,
Eva Kugelmann, Gerd Folkers, and Ulrike Holzgrabe
Part III
drug desIgn, ChemICal and moleCular
asPeCts of drug aCtIon
Chapter 12 Discovery.of.Potent.and.Selective.Inhibitors.of.Human.
Aldosterone.Synthase.(CYP11B2):.A.New.Target.for.the.
Treatment.of.Congestive.Heart.Failure.and.Myocardial.
Fibrosis—A.Review..........................................................................165
R. W. Hartmann, U. Müller-Vieira, S. Ulmschneider,
and M. Voets
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Contents ii
Chapter 13 Thiocarboxanilides:.A.New.Class.of.Nonnucleoside.Reverse.
Transcriptase.Inhibitors.(NNRTIs).with.Great.Potential.for.the.
Treatment.of.Human.Immunodeficiency.Virus.Type.1.(HIV-l).
Infections...........................................................................................177
E. De Clercq, A. Karlsson, and J. Balzarini
Chapter 14 Histamine.H -Receptor.Agonists.and.Antagonists:.Chemical,.
3
Pharmacological,.and.Clinical.Aspects............................................199
Holger Stark and Walter Schunack
Chapter 15 Anti-Inflammatory.Actions.of.Flavonoids.and.Structural.
Requirements.for.New.Design..........................................................215
Theoharis C. Theoharides
Chapter 16 Molecular.Mechanisms.of.H O -Induced.DNA.Damage:..
2 2
The.Action.of.Desferrioxamine........................................................227
M. Tenopoulou, P.-T Doulias, and D. Galaris
Chapter 17 LNA.(Locked.Nucleic.Acid).and.Functionalized.LNA:..
Toward.Efficient.Gene.Targeting......................................................239
Jesper Wengel
Part IV
drug – XenoBIotIC metaBolIsm
Chapter 18 The.Effect.of.Diet.on.Drug.Metabolism...........................................247
K.J. Netter
Chapter 19 Cytochromes.P450.in.the.Metabolism.and.Bioactivation.of.
Chemicals..........................................................................................253
Costas Ioannides
Chapter 20 In Vitro.Methods.to.Measure.Drug.Metabolism.and.Drug.
Interactions.in.Drug.Discovery.and.Development............................273
O. Pelkonen, M. Turpeinen, J. Uusitalo, P. Taavitsainen,
and H. Raunio
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iii Chemistry and Molecular Aspects of Drug Design and Action
Part V
PhysICal organIC and theoretICal
medICInal ChemIstry
Chapter 21 How.to.Probe.the.Sites.of.Action.of.Drug.Molecules.......................289
A. Makriyannis and F. Bitter
Chapter 22 Physicochemical.Profiling.in.Early.Drug.Discovery:..
New.Challenges.at.the.Age.of.High-Throughput.Screen.and.
Combinatorial.Chemistry..................................................................303
Bernard Faller
Chapter 23 Drug–Membrane.Interaction.and.Its.Importance.for.Drug.
Efficacy..............................................................................................313
J.K Seydel, E.A. Coats, K. Visser, and M. Wiese
Chapter 24 The.Fight.Against.AIDS:.New.Avenues.for.Inhibiting.Reverse.
Transcriptase.(RT),.an.Old.Target....................................................325
Maurizio Botta, Lucilla Angeli, Marco Radi, and Giovanni Maga
Index.......................................................................................................................347
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Editors
Eleni A. Rekka is.an.associate.professor.in.pharmacy,.Department.of.Pharmaceuti-
cal.Chemistry,.School.of.Pharmacy,.Aristotelian.University.of.Thessaloniki,.Greece..
She.holds.a.first.degree.in.pharmacy.(1977).and.a.Ph.D..in.medicinal.chemistry.
(1986),.both.from.the.School.of.Pharmacy,.Aristotelian.University.of.Thessaloniki..
Since.1978.her.research.activities.in.the.department.have.been.in.the.fields.of.design.
and.synthesis.of.novel.biologically.active.compounds,.including.in vivo.and.in vitro.
investigations,.aimed.at.the.elucidation.of.the.molecular.mechanism.of.action.and.
the.establishment.of.relationships.between.chemical.structure.and.biological.activ-
ity..Special.areas.of.scientific.and.research.interest.are.those.of.free.radicals,.and.
oxidative.stress.and.antioxidant.agents,.in.relation.to.the.design.of.bioactive.com-
pounds.for.the.treatment.of.conditions.such.as.inflammation.and.atheromatosis..An.
important.part.of.her.activity.covers.xenobiotic.metabolism..For.the.last.30.years,.
she.has.participated.in.the.teaching,.research,.and.administrative.activities.of.the.
department..She.has.written.a.number.of.publications.in.scientific.journals,.and.has.
given.many.presentations.at.international.conferences.
She.has.conducted.research.as.a.visiting.scientist.on.topics.in.her.specialty.in.
the.following.European.research.institutes:.Department.of.Pharmacochemistry,.Free.
University.of.Amsterdam.(1987–1988);.Janssen.Research.Foundation,.Beerse,.Bel-
gium.(1989);.School.of.Biological.Sciences,.University.of.Surrey,.Guildford,.UK.
(1992);.Department.of.Pharmacology.and.Therapeutics,.University.of.Sheffield,.UK.
(1994);.Department.of.Pharmacology.and.Toxicology,.Philipps.University,.Marburg,.
Germany.(1995);.University.of.Mainz,.Germany.(1997);.School.of.Pharmacy,.Cath-
olic.University.of.Louvain,.Brussels,.Belgium.(1999);.Université.Rene.Descartes.
(Paris.V),.Unité.mixte.des.recherché.NRS,.Paris,.France.(2001).
Panos N. Kourounakis.is.professor.emeritus.in.pharmacy,.Department.of.Pharma-
ceutical.Chemistry,.School.of.Pharmacy,.Aristotelian.University.of.Thessaloniki,.
Greece..He.graduated.from.the.Department.of.Pharmacy,.University.of.Athens,.and.
obtained.his.Ph.D..in.pharmaceutical–medicinal.chemistry.from.Chelsea.College.of.
Science.and.Technology,.University.of.London..He.also.did.postdoctoral.research.in.
drug.metabolism.at.Chelsea.College..He.served.as.a.research.associate.in.medicinal.
chemistry,.Faculty.of.Pharmacy,.University.of.Montreal,.where.he.became.head.of.
the.biochemical.laboratory.and.assistant.professor,.Institute.of.Experimental.Medi-
cine.and.Surgery,.Faculty.of.Medicine..He.became.professor.of.pharmaceutical.
chemistry,.School.of.Pharmacy,.Aristotelian.University.of.Thessaloniki,.Greece,.
then.head.and.deputy.head..For.about.20.years.he.was.director.of.the.department..
Since.2003.he.has.been.professor.emeritus.
Dr..Kourounakis.is.a.member.of.the.council.of.the.National.Drug.Organisation,.
and.has.been.both.president.and.vice.president.of.the.scientific.committee.for.the.
approval.of.medicines.in.Greece..He.was.a.member.of.the.Supreme.Health.Council.
ix
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