Curriculum Vitae Camille G. Wermuth                15/10/01

CURRICULUM VITAE

 

PROFESSOR CAMILLE-GEORGES WERMUTH

 

            Camille-Georges Wermuth studied Pharmacy and Chemistry at the Strasbourg University (Professor J. Schreiber and G. Ourisson) and did his PhD in Organic Chemistry on "Directed Aldol Condensation between Enolisable Aldehydes and alpha-Ketocarboxylic Acids" (1964). He became interested in Medicinal Chemistry during his two years military service in the French Navy at the "Centre d'Études Physiobiologiques Appliquées à la Marine" in Toulon. At that time this Research Center was directed by the famous surgeon Dr Henri Laborit, the inventor of artificial hibernation and of chlorpromazine.

Dr Wermuth is Professor of Organic Chemistry and Medicinal Chemistry at the Faculty of Pharmacy, Louis Pasteur University, Strasbourg, France since 1969 and did a two-month research stay in W.S. Johnson’s Laboratory at the Stanford University in 1975. He also created and headed for 27 years the Molecular Pharmacochemistry Unit of the CNRS (“Centre National de la Recherche Scientifique”). This unit is original in that it has three areas of responsibility: synthetic organic chemistry, medicinal chemistry and computer modeling. Research is essentially concentrated upon neuro-psychiatric pathologies; this has led to the development and synthesis of many research tools for the neurosciences and the development of a new psychotropic drug, minaprine, marketed in Europe since 1980.

            Professor Wermuth’s main research themes focus on the chemistry and the pharmacology of pyridazine derivatives. Particularly, the 3-aminopyridazine pharmacophore allowed him to accede to an impressive variety of biological activities. Among them one can cite:

·       antidepressant and anticonvulsant molecules;

·       inhibitors of enzymes such as mono-amine-oxidases, phosphodiesterases and acetylcholinesterase;

·       ligands for neuro-receptors: GABA-A receptor antagonists, serotonine 5-HT3 receptor antagonists, dopaminergic and muscarinic agonists;

            Very recently, in collaboration with the scientists of the Sanofi company, he developed potent antagonists of the 41 amino-acid neuropeptide CRF (coticotrophin-releasing factor) which regulates the release of ACTH and thus the synthesis of corticoids in the adrenal glands.

            Another interest of Professor Wermuth, in collaboration with Professor Jean-Charles Schwartz and Doctor Pierre Sokoloff (INSERM, Paris) resides in the development of selective ligands of the newly discovered dopamine D3 receptor. After a three-year exploratory phase, this research has led to nanomolar partial agonists which may prove useful in the treatment of the cocaine-withdrawal syndrome.

            Besides about 250 scientific papers and about 55 patents, Professor Wermuth is co-author or editor of several books (Pharmacologie Moléculaire, Masson & Cie, Paris; Médicaments Organiques de Synthèse, Masson & Cie, Paris; Medicinal Chemistry for the 21st Century, Blackwell Scientific Publications, Oxford; Trends in QSAR and Molecular Modeling, ESCOM, Leyden etc.).

            His last book entitled "The Practice of Medicinal Chemistry" was published by Academic Press in February 1996. It originated from the recognition that the majority of medicinal chemists working in the pharmaceutical industry are organic synthetic chemists with little or no background in medicinal chemistry who have to acquire the specific aspects of medicinal chemistry during their early years in the pharmaceutical industry. It was therefore precisely aimed to be their "bedside book" at the beginning of their career. Effectively it is called « The Bible » by many medicinal chemists! Given its success, it was rapidly sold out and a second printing has been undertaken, it has also been translated into Japanese in 1998, an Italian and a Chinese translation are underway.

            Professor Wermuth has been awarded the Charles Mentzer Prize of the Société Française de Chimie Thérapeutique in 1984, the Léon Velluz Prize of the French Academy of Science in 1995, the Prix de l’Ordre des Pharmaciens 1998 by the French Academy of Pharmacy and the Carl Mannich Prize of the German Pharmaceutical Society in 2000. He is Corresponding Member of the German Pharmaceutical Society and was nominated Commandeur des Palmes Académiques in 1995. He has been President of the Medicinal Chemistry Section of the International Union of Pure and Applied Chemistry (IUPAC) from 1988 to 1992 and since January 1998 is President of the IUPAC Division on Chemistry and Human Health.

 

His address:

Faculté de Pharmacie,

Université Louis Pasteur, Strasbourg,

74, Route du Rhin, 67401 ILLKIRCH-Cedex, France

E-mail: <wermuth@aspirine.u-strasbg.fr>

 


 

PROFESSOR C.G. WERMUTH AND HIS TEAM :

 

List of some useful or outstanding contributions.

 

1965:     Acetylamino-succinic acid, dipotassium salt, COGITUM® (SmithKline-Beecham)

             Prodrug of aspartic acid.

             Neth. Pat. Appl. 6 503 883, Sept. 27, 1965; Chem. Abst. 1966, 64, 4945 c.

 

1971:     N-Acetyl-L-hydroxyproline, JONCTUM® (Hoechst Marion Merrel)

                          Prodrug of L-hydroxy-proline.

                          Brit. Pat. 1 246 141, Sept. 15, 1971; Chem. Abst. 1971, 75, 140 679 b

 

1974:     Succinoyl-tri-L-Ala-para-nitranilide.

             Substrate for the determination of elastase. Todays a classical in biochemical reagents catalogues.

             J. Bieth, B. Spiess and C.G. Wermuth, Biological Medecine, 1974, II,    350.

 

1977:     N-Trifluoroacetyl-L-alanyl-L-alanine para-nitranilide.

             Potent inhibitor of pancreatic elastase.

             1. J. Bieth, J.L. Dimicoli and C.G. Wermuth, French Pat. 770471-3, Feb. 18, 1977.

            2. P.Lestienne, J.L. Dimicoli, C.G. Wermuth and J. Bieth, Biochem. Biophys. Acta, 1981, 658, 413.

 

1977:     IPS 339 or (3-tert-butylamino-2-hydroxy)-propyl-9-oximinofluorene.

             Selective beta-2 blocker. Universally used as reference compound.

            J.L. Imbs, F. Miesch, J. Schwartz, J. Velly, G. Leclerc, A. Mann and C.G. Wermuth, Brit. J. Pharmacol., 1977, 60, 357.

 

1978:     2-[4-(N-2-chloroethyl-N-methyl-aminomethyl)-2,6-dichlorophenyl]-imino-imidazoline.

             First example of an irreversible alpha-2 agonist.

1.       B. Rouot and G. Leclerc, Eur. J. Med. Chem., 1978, 13, 521

2.       G. Leclerc, B; Rouot, J.Schwartz, J. Velly and C.G. Wermuth, Brit. J. Pharmacol., 1980, 71, 5.

 

1979:     Gamma-ethoxybutyrolactone (GEB) and succinic semialdehyde (SSA).

            An easy synthesis of gamma-ethoxybutyrolactone (GEB) was found; GEB yields quantitatively succinic semialdehyde (SSA) when heated with distilled water. SSA is a CNS metabolite of GABA and acts as substrate for the SSA-reductase and the SSA-deshydrogenase.

            C.G. Wermuth, J. Org. Chem. 1979, 44, 2406.

 

 

1979: Para-amino-clonidine and [3H]-para-amino-clonidine.

            Potent alpha-mimetic agent (pD2 : 11.2 on rat aorta). The tritiated analogue is much more stable than [3H]-noradrenaline. Compounds now commercially available (RBI, NEN, CEA).

            1. B. Rouot and S.H. Snyder, Life Sci., 1979, 25, 769.

            2. G. Leclerc, B. Rouot, J. Schwartz, J. Velly and C.G. Wermuth, Brit. J. Pharmacol., 1980, 71, 5.

 

1980: Minaprine or [3-(N-(2-morpholinoethyl)-6-phenyl-4-methyl-pyrid-azinamine. dihydrochloride], CANTOR®, ISOPULSAN®, CAPRIM®.

Atypical antidepressant devoid of noradrenergic and anticholinergic properties. Synthesized in 1968 and launched in 1980.

1. C.G. Wermuth and A. Exinger, Agressologie, 1972, 13(5), 285.

2. C.G. Wermuth, G. Schlewer, J.J. Bourguignon, G. Maghioros, M.J.   Bouchet, C. Moire, J.P. Kan, P. Worms and K. Bizière, J. Med. Chem., 1989,  32 , 528.

 

1982: Discovery of binding sites for gamma-hydroxy butyrate (GHB).

Gamma-hydroxy butyric acid possesses specific binding sites which are not recognized by the closely related gamma-amino butyric acid (GABA).

1. J. Benavides, J.F. Rumigny, J.J. Bourguignon, C. Cash, C.G. Wermuth, P. Mandel,  G. Vincendon and M. Maitre, Life Sci., 1982, 30, 953.

2. J. Benavides, J.F. Rumigny, J.J. Bourguignon, C.G. Wermuth, P.Mandel, G. Vincendon and M. Maitre, J. Neurochem.1982, 38, 1570.

 

1987: Discovery of a new class of selective antagonists for the GABAA receptors.

Gabazine is a potent, selctive, competitive, chemically stable and water-soluble antagonist for the GABAA receptor.

1. Wermuth, C.G., Bourguignon, J.-J., Schlewer, G., Gies, J.P., Schoenfelder, A., Melikian, A., Bouchet, M.-J., Chantreux, D., Molimard, J.-C., Heaulme, M., Chambon, J.-P. and Bizière, K. J. Med. Chem., 1987; 30; 239-249.

2. Rognan, D., Boulanger, T., Hoffmann, R., Vercauteren, D.P., André, J.M., Durant, F.and Wermuth, C.G. J. Med. Chem., 1992; 35; 1969-1977.

 

1989: Structure-activity relationships elucidation of the Rolipram-derived phosphodiesterase IV inhibitors .

A systematic study of rolipram analogues allows the identification of the pharmacophoric elements associated with phosphodiesterase IV inhibition.

Marivet, M.C, Bourguignon, J.-J., Lugnier, C., Mann, A., Stoclet, J.-C. and Wermuth, C.G. J. Med. Chem., 1989, 32, 1450-1457.

 

 

1991-1993: Discovery of a new class of muscarinic agonists.

SR 46559A or 3-(N-(2-diethylamino-2-methylpropyl)-6-phenyl-5-propyl-pyridazine sesquifumarate is an agonist of the central muscarinic receptors. Developed whith Elf-Sanofi, this compound is presently undergoing phase II clinical trials in Alzheimer patients.

1. Wermuth, C.G., Bourguignon, J.J., Hoffmann, R., Boigegrain, R., Brodin, R., Kan, J.P.and  Soubrié, P. Bioorg . MedChem . Lett . 1992, 2 , 833-838.

2. J.P. Kan, R. Steinberg, F. Oury-Donat, J.C. Michaud, O. Thurneyssen, J.P. Terranova, C. Gueudet, J. Souilhac, R. Brodin, R. Boigegrain, C.G. Wermuth, P. Worms, P. Soubrié and G. Le Fur, Psychopharmacology, 1993, 112, 219-227.

 

1994 : Discovery of metabotropic glutamate receptor ligands

LY-307 452 or 2-amino-4-(4'4'-diphenylbutyl)-pentane dioic acid (1994): Selective antagonist of the  cAMP-coupled metabotropic glutamic acid receptors.

J. Ezquerra, A. Rubio, A. Mann, A. Schoenfelder, D.D. Schoepp, C. Pedregal, C.G. Wermuth

Gamma glutamates, new patent application. British Patent N° 9324872, 3 Dec. 1993.

A.R. Esteban, A. Mann, A. Schoenfelder, D.D. Schoepp, C.P. Tercero & C.G. Wermuth

Aspartic acid derivatives of homologues thereof and their use in the treatment of neurological diseases. European Patent N° 0 656 345 A1, ELI-LILLY, 2.Dec.1994.

 

1992-1999: Selective antagonists of CRF receptors.

A series of aryl-substituted aminothiazoles derived from minaprine are potent and selective antagonists of the corticotrophin releasing factor (CRF).

D. Gully, P. Roger, G. Valette, C;G. Wermuth, G. Courtemanche & C. Gauthier

Dérivés alkylamino ramifiés du thiazole, leurs procédés de préparation et les compositions pharmaceutiques qui les contiennent. Demande de Brevet Français N°9207736, ELF-SANOFI, 24 june 1992.

D. Gully, P. Roger & C.G. Wermuth, Dérivés de 4-phénylaminothiazole, leur procédé de préparation et les compositions pharmaceutiques les contenant. Demande de Brevet Français N° 9507437, SANOFI, 21 june 1995.

 

1992-1999: Selective ligands for dopamine D3 receptors.

Nafadotride [DO-779 or N-[2-(1-butylpyrrolidinyl) methyl]-1-methoxy-4-cyano- naphtalene 2-carboxamide] is a selective antagonist of D3 dopaminergic receptors.

C.G. Wermuth, A. Mann, F. Garrido, J.M. Lecomte, J.C. Schwartz and P. Sokoloff, New derivatives of naphtamide-2 and their therapeutic applications. France priority by 11/12/95 N°95 14654. PCT FR 96 402672-8-2101 vy 06/02/97. US Patent N° 08/762,782 by 02/04/98.

 

BP 897, a partial dopamine D3 receptor agonist, [N-1-(o-methoxyphenyl)-N-4-(naphtyl-2-carboxamidobutyl)-piperazine], allows selective inhibition of cocaine-seeking behaviour.

M. Pilla, S. Perrachon, F. Sautel, F. Garrido, A. Mann, C.G. Wermuth, J.-C. Schwartz, B. Everitt, & P. Sokoloff, Nature, 400:371-375 (1999).

 

RESEARCH TOOLS :

a) Tritiated molecules :

             [3H]-Para-amino-clonidine (1979): Alpha-2 receptor marker.

             [3H]-Minaprine (1984): Atypical 5-HT-receptor marker.

             [3H]-S-Azidosulpride (1987):  Photoaffinity marker for D2 dopaminergic receptors.

             [3H]-S-DO-710 (1987) : Selective D2 receptor antagonist.

[3H]-Gabazine ou SR 95531: (1987): Selective, potent reversible and chemically stable GABA-A.receptor antagonist.

[3H]- Trans-hydroxycrotonic acid (1989) : Endogenous ligand of the gamma-hydroxybutyrate binding sites.

b) Non-tritiated molecules :

Succinoyl-tri-L-Ala-para-nitranilide (1974): Substrate for elastase determination, now a classical in the biochemical reagents catalogues.

N-Trifluoroacetyl-L-alanyl-L-alanine para-nitranilide (1977): Potent inhibitor of  pancreatic elastase.

PS 339 or 9-[(3-tert-butylamino-2-hydroxy)-propyl-oximino]-fluorene (1977) : Selective antagonist of beta-2 receptors.

4-(N-2-chloro-ethyl-N-methyl-aminoethyl)-2,6-dichloro-phenyl-2-imino-imidazoline (1978) : First exemple of an alpha-2 irreversible antagonist.

SSA or Succinic semi-aldehyde  (1979): Synthesis of a chemically stable precursor producing instantly SSA solutions by simple heating with distilled water. SSA is a metabolite of GABA and a  substrate of the enzymes SSA-reductase and SSA-deshydrogenase.

Gabazine ou SR 95531 (1985): Selective, potent reversible and chemically stable GABA-A.receptor antagonist.

SR 95639A, a tricyclic minaprine analogue (1989): Selective agonist  of muscarinic M1 receptors.

N-Pivaloyl-o-toluidine et N-pivaloyl-o-benzylaniline (1989): Reagents for the direct determination of organo-lthium derivatives. Presently reference N°34,906.2 of the Aldrich catalogue.

 NCS-382 or  trans-(5-hydroxy-6,7,8,9-tetrahydro-[5H]-benzo- cycloheptene-6-yl) acetic acid (1990): First competitive antagonist of gamma-hydroxybutyrate receptors.

NCS-1044 or 3-bromo-2-(3-chlorophenyl)-6-(N-methyl-N-phenyl-acetamido)-oxo-5,6-dihydro imidazo[1,2-c]-quinazoline (1990): Highly potent and selective ligand of the peripheral benzodiazepine receptors.

LY-307 452 or 2-amino-4-(4'4'-diphenylbutyl)-pentane dioic acid (1994): Selective antagonist of the cAMP-coupled metabotropic glutamic acid receptors.