Table Of ContentCRC Handbook
of
PAF and
PAF Antagonists
Editor
Pierre Braquet
Directeur General/Directeur de la Recherche
Institut Henri Beaufour
Le Plessis Robinson, France
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PREFACE
PAF-acether is a phospholipid mediator of allergy and inflammation whose structure is
1-O-alkyl-2(R)-acetyl-glyeery 1-3-phosphocholine. It originates from membrane ether lipid
via the successive involvement of phospholipase A2 (that generates the inactive precursor,
lyso-PAF) and acetyltransferase, the latter enzyme being activated by a phosphorylation
process. PAF-acether is inactivated by membrane and plasma acetylhydrolyse. PAF-acether
is generated by various cell types such as polymorphonuclear (PMN) basophils, neutrophils,
and eosinophils, monocytes/macrophages, platelets, endothelial cells, mast cells, and organs
including kidney and heart.
In vitro, PAF-acether triggers platelet and PMN aggregation and degranulation, induces
the generation of arachidonic acid metabolites from various cell types, and inhibits lym-
phocyte proliferation and interleukin 2 production. In vivo, PAF-acether causes broncho-
constriction, bronchial hyperreactivity to various agonists, hypotension, thrombocytopenia
and leukopenia, increase in vascular permeability, gastrointestinal damages and acute renal
failure. PAF-acether acts via specific binding sites present on platelet, neutrophil, and tissue
membranes. Recently, several PAF-acether antagonists have been described including struc-
ture-related and -unrelated substances. Some of them, such as BN 52021 and BN 52063,
are already in clinical trials as antiasthma drugs and extensive studies with these and newly
developed compounds will help to determine the actual role of the mediator in health and
diseases.
CONTRIBUTORS
Evelyne Audry Otto R. Gottlieb
Laboratoire de Chimie Analytique Professor
Faculté de Pharmacie Instituto de Quimica
Bordeaux, France Universidade de Sâo Paulo
Sâo Paulo, Brazil
Pierre Braquet
Directeur Général/Directeur de la Recherche Gunnar Grue-Sprensen
Institut Henri Beaufour Chemical Research Department
Le Plessis Robinson, France Leo Pharmaceutical Products
Ballerup, Denmark
Colette Broquet
Masashi Hashimoto
Director, Department of Chemistry
Director of Exploratory Research Lab
Institut Henri Beaufour
Fujisawa Pharmaceutical Co.
Les Ulis, France
Tsukuba, Ibaraki, Japan
Jean-Claude Colleter
Keiji Hemmi
Laboratoire de Chimie Analytique
Head of Chemistry
Faculté de Pharmacie
Exploratory Research Lab
Bordeaux, France
Fujisawa Pharmaceutical Co.
Tsukuba, Ibaraki, Japan
F. Croizet
Laboratoire de Chimie Analytique Hubert O. Heuer
Faculté de Pharmacie Head of Laboratory
Bordeaux, France
Department of Pharmacology
Boehringer Ingelheim KG
Philippe Dallet Ingelheim/Rhein, Germany
Laboratoire de Chimie Analytique
Faculté de Pharmacie David Hosford
Bordeaux, France Director of Communications
Institut Henri Beaufour
J. P. Dubost Le Plessis Robinson, France
Professeur
William J. Houlihan
Laboratoire de Chimie Analytique
Director, Chemical Research
Faculté de Pharmacie
Sandoz Pharmaceuticals
Bordeaux, France
East Hanover, New Jersey
André Esanu
Matyas Koltai
Institut Henri Beaufour
Institut Henri Beaufour
Le Plessis Robinson, France
Le Plessis Robinson, France
Annie Etienne Marie-Hélène Langlois
Director, Department of Pharmacology Laboratoire de Chimie Analytique
Institut Henri Beaufour Faculté de Pharmacie
Les Ulis, France Bordeaux, France
Daniel Lavé Norihiko Shimazaki
Département de Chimie Researcher of Chemistry
Centre de Recherches de Vitry Exploratory Research Lab
Rhône-Poulenc Santé Fujisawa Pharmaceutical Co.
Vitry sur Seine, France Tsukuba, Ibaraki, Japan
Jean-Michel Mencia-Huerta Muneo Takatani
Director, Department of Immunology Research Scientist
Institut Henri Beaufour Chemistry Research Laboratories
Les Ulis, France Takeda Chemical Industries, Ltd.
Osaka, Japan
Christian Kaergaard Nielsen
Department of Pharmacology Jefferson W. Tilley
Leo Pharmaceutical Products Research Leader
Ballerup, Denmark Chemistry Research Department
Hoffmann La Roche
Margaret O’Donnell Nutley, New Jersey
Department of Pharmacology
and Chemotherapy Caroline Touvay
Hoffmann La Roche Head of Laboratory
Nutley, New Jersey Department of Immunology
Institut Henri Beaufour
Masanori Okamoto Les Ulis, France
Head, Allergy and Inflammation Research
Exploratory Research Lab Susumu Tsushima
Fujisawa Pharmaceutical Co. Research Head
Tsukuba, Ibaraki, Japan Chemistry Research Laboratories
Takeda Chemical Industries, Ltd.
Bernadette Pignol Osaka, Japan
Head of Laboratory
Department of Immunology Keizo Yoshida
Institut Henri Beaufour Head of Pharmacology
Les Ulis, France New Drug Research Lab
Fujisawa Pharmaceutical Co.
Paulete Romoff Osaka, Japan
Instituto de Química
Universidade de Sao Paulo Massayoshi Yoshida
Sao Paulo, Brazil Instituto de Química
Universidade de Sao Paulo
Ichiro Shima Sâo Paulo, Brazil
Researcher of Chemistry
Exploratory Research Lab
Fujusawa Pharmaceutical Co.
Tsukuba, Ibaraki, Japan
TABLE OF CONTENTS
PART Is NATURAL PAF ANTAGONISTS
Chapter 1
Recent Progress in PAF Antagonist Research.........................................................................3
Matyas Koltai, David Hosford, André Esanu, and Pierre Braquet
Chapter 2
PAF Antagonists From Microbial Origin: Structure-Activity Relationship of Diketopiperazine
Derivatives....................................................................................................................................71
Keiji Hem mi, Norihiko Shimazaki, Ichiro Shima, Masanori Okamoto, Keizo Yoshida,
and Masashi Hashimoto
Chapter 3
Kadsurenone Type Neolignans, Potential PAF Antagonists: Chemistry and
Distribution....................................................................................................................................81
Otto R. Gottlieb, Massayoshi Yoshida, and Paulete Romoff
PART II: SYNTHETIC PAF ANTAGONISTS
Chapter 4
Structure Activity Relationships in CV-3988 and CV-6209 PAF Antagonists Series .... 97
Muneo Takatani and Susumu Tsushima
Chapter 5
Aminoacylates and Aminocarbamates of 2-Substituted 4-Hydroxymethyl 1,3-Dioxolans:
Structure Activity Relationships and Biological Activity as PAF-Antagonists..................119
Colette Broquet, Annie Etienne, Caroline Touvay, Bernadette Pignol, Jean-Michel
Mencia-Huerta, and Pierre Braquet
Chapter 6
GS 1065-180 and Related PAF Antagonists: Chemistry and Pharmacology......................135
Gunnar Grue-S0rensen and Christian Kaergaard Nielsen
Chapter 7
Structure Activity Relationships in Cyclic Analogs of PAF with PAF Antagonist
Properties......................................................................................................................................157
William J. Houlihan
Chapter 8
Pharmacology of Hetrazepines as PAF-Antagonists.............................................................171
Hubert O. Heuer
Chapter 9
Structure-Activity Relationships in Pyrrolo[l ,2-c]Thiazoles PAF Receptor
Antagonists..................................................................................................................................203
Daniel Lavé
Chapter 10
Structure Activity Relationships in 5-Aryl-2,3-Dihydroimidazo[2,la]Isoquinoline pa f
Antagonists..................................................................................................................................221
William J. Houlihan
Chapter 11
A-[<i)-(Heteroaryl)Alkyl]Carboxamide Derivatives as Platelet Activating Factor Antagonists:
Structure-Activity Relationships and Biological Data...........................................................229
Jefferson W. Tilley and Margaret O’Donnell
PART III: MOLECULAR MODELING
Chapter 12
Structure Activities in PAF Acether Antagonist Series Using Molecular Lipophilic Potential
Studies.........................................................................................................................................261
J. P. Dubost, M. H. Langlois, E. Audry, P. Braquet, J. C. Colleter, F. Croizet, and
Ph. Dallet
Index............................................................................................................................................271
Part I
Natural PAF Antagonists
