Camille G.
Wermuth
Prestwick Chemical Inc., Boulevard Gonthier d'Andernach, 67400, ILLKIRCH, France. E-mail: camille.wermuth@prestwickchemical.fr
First published on 10th June 2011
One can estimate that about 50% of all the drug molecules used in medicine contain a phenyl ring which can be substituted or not. The bioisosteric replacement of these phenyl rings by the corresponding COMPOUND LINKS
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Download mol file of compoundpyridazine rings opens an access to several thousands of diaza analogues presenting more interaction possibilities, lower Log P values and improved crystalline salts. The use of COMPOUND LINKS
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Download mol file of compoundpyridazine scaffolds in place of phenyl scaffolds entails additional interaction possibilities. Another interest of pyridazines is their capacity to act as original functional surrogates. Thus, aminopyridazines can be used as carboxamide, as well as amine surrogates. Finally, the many examples of pyridazines used either as a structural element or as a main scaffold, justify largely their status as privileged structures
Fig. 1 Directed aldolization between COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyruvic acid and COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundn-butanal. |
The treatment of the semisuccinic aldehydo-acid 3 with COMPOUND LINKS
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Download mol file of compoundhydrazine yielded the COMPOUND LINKS
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Download mol file of compoundhydroxy-pyridazinoneCOMPOUND LINKS
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Download mol file of compound4 which was easily dehydrated to the COMPOUND LINKS
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Download mol file of compoundmethyl-ethyl pyridazoneCOMPOUND LINKS
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Download mol file of compound5 (“MEP”) (Fig. 2).
Fig. 2 Preparation of the COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundmethyl-ethyl-pyridazoneCOMPOUND LINKS Read more about this on ChemSpider Download mol file of compound5 (“MEP”). |
As I had already an ongoing research program on COMPOUND LINKS
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Download mol file of compoundGABA and COMPOUND LINKS
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Download mol file of compoundγ-hydroxybutyrate with Henri Laborit, the inventor of COMPOUND LINKS
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Download mol file of compoundchlorpromazine, I provided him with a sample of MEP with the hope that he would detect some interesting biological activity. A preliminary pharmacological study, based essentially on isolated organs and on EEG investigations,3 revealed some hypotensive activity. Henri Laborit decided then to proceed to some clinical assays. In humans no hypotensive activity was observed. However, three weeks after the injection of MEP one of the patients wrote a letter to Dr Laborit expressing her warmest thanks for the MEP treatment “which removed her shoulder ache”. Laborit therefore asked me if the MEP molecule did show any analogy with an already existing analgesic agent. Effectively this was the case insofar that the COMPOUND LINKS
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Download mol file of compoundpyridazone ring of MEP could be compared to the typical COMPOUND LINKS
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Download mol file of compoundpyrazolone functionality of COMPOUND LINKS
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Download mol file of compoundantipyrine (Fig. 3).
Fig. 3 The COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridazone ring of compound COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound5 shows some similitude with the analgesicdrugCOMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundantipyrineCOMPOUND LINKS Read more about this on ChemSpider Download mol file of compound6. This analogy is even more pronounced with N-phenyl analogue 7. However, N-phenyl-MEP7 is quasi insoluble in COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundwater. |
This unexpected pharmacological activity of MEP was the starting-point of a long term research activity in COMPOUND LINKS
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Download mol file of compoundpyridazine chemistry and medicinal chemistry. With my students and coworkers we examined more than one thousand COMPOUND LINKS
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Download mol file of compoundpyridazine derivatives. Our main goal was to prepare compounds exhibiting enough biological activity to become drug candidates. The choice of pyridazines appeared to be timely because the chemistry of this heterocycle and its use in drug design were not very much explored.
Fig. 4 Historical COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridazinedrugs. |
Two review articles written by Heinisch and Frank analyse the COMPOUND LINKS
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Download mol file of compoundpyridazine medicinal chemistry publications covering the period between 1975 and 1998.4,5 Clearly it appears that the results in terms of achieving marketable COMPOUND LINKS
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Download mol file of compoundpyridazinedrug molecules were very modest and that none of the launched compounds reached the blockbuster status. A Google Scholar comparative examination of the “COMPOUND LINKS
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Download mol file of compounddiazinedrug” consultations highlights the dominant position of the pyrimidines which have about ten times more entries than the pyridazines. As an example the entry “COMPOUND LINKS
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Download mol file of compoundpyridazinedrugs” accounts for only 10100 hits as compared to 141000 hits for the entry “COMPOUND LINKS
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Download mol file of compoundpyrimidinedrugs”. A similar ratio is found with the entry “COMPOUND LINKS
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Download mol file of compoundaminopyridazinedrugs” (21400 hits) as compared with the “COMPOUND LINKS
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Download mol file of compoundaminopyrimidinedrugs” (28600 hits). A possible explanation may reside in the almost complete absence of pyridazines in living organisms whereas pyrimidines play an extremely important role in biology as constituents of nucleic acids, of COMPOUND LINKS
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Download mol file of compoundATP and various low molecular derivatives. Another point is the very modest place of the pyridazines in natural product chemistry as illustrated below.
Fig. 5 The structure of pyridazomycin10. |
The proposed pyridazomycinbiosynthesis7 involves the incorporation of the COMPOUND LINKS
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Download mol file of compoundornithine δ-amino function into a COMPOUND LINKS
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Download mol file of compoundpyridazine scaffold which itself results from a succession of cyclization and several dehydrogenations of COMPOUND LINKS
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Download mol file of compoundornithine (Fig. 6). The biosynthesis of pyridazomycin is highly dependent on the availability of ornithine residues.
Fig. 6 The COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridazine ring system of pyridazomycin results from a succession of cyclization and several dehydrogenation steps. |
COMPOUND LINKS
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Download mol file of compoundOrnithine is not an amino acid coded for by DNA and, in that sense, is not involved in protein synthesis. However, in mammalian non-hepatic tissues, the main use of the urea cycle is in arginine biosynthesis, so, as an intermediate in metabolic processes, COMPOUND LINKS
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Download mol file of compoundornithine is quite important. It is believed not to be a part of genetic code because polypeptides containing unprotected ornithines undergo spontaneous lactamisation. The double necessity to start from COMPOUND LINKS
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Download mol file of compoundornithine and to create an N–N bond explains the small number of natural pyridazines. Beside pyridazomycin, azamerone 11 is the second natural product known to contain a COMPOUND LINKS
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Download mol file of compoundpyridazine ring. The terpenoidCOMPOUND LINKS
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Download mol file of compoundphthalazinone azamerone was isolated from the marine sediment-derived bacterium Streptomyces sp. CNQ-766 (Fig. 7).8
Fig. 7 The key step of the biosynthesis of azamerone is the transformation of the COMPOUND LINKS Read more about this on ChemSpider Download mol file of compounddiazoketone11 into the COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridazoneCOMPOUND LINKS Read more about this on ChemSpider Download mol file of compound12. |
It was first speculated that the COMPOUND LINKS
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Download mol file of compoundpyridazine ring moiety in azamerone was also derived from the cyclization of amino acid residues, but biosynthetic investigations of azamerone7 suggested that azamerone may rather be derived from a COMPOUND LINKS
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Download mol file of compoundnaphthoquinone precursor (Fig. 7).
Antrimycin 9 and cirratiomycins are dihydropyridazines. Antrimycin13, Fig. 8 (R = CH3), was isolated from Streptomyces xanthocidicusMG-125-CF1, and shows activity in vitro against Mycobacterium smegmatis and Mycobacterium tuberculosis. Cirratiomycin A 14, Fig. 8 (R = iso-Bu), was isolated from Streptomyces cirratus248-Sq2, and is active in vitro against a narrow range of Lactobacilli and some strains of Streptococcus.10
Fig. 8 Structures of the partially saturated dihydropyridazines: antrimycin (R = CH3) and cirratiomycin A (R = iso-Bu). |
Also a COMPOUND LINKS
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Download mol file of compounddihydropyridazinedrug candidate is compound L 365209 COMPOUND LINKS
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Download mol file of compound15, a structurally unique, potent, and selective COMPOUND LINKS
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Download mol file of compoundoxytocinantagonist derived from Streptomyces silvensis (Fig. 9).11
Fig. 9 Structure of the COMPOUND LINKS Read more about this on ChemSpider Download mol file of compounddihydropyridazine L 365209 COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound15. |
Fig. 10 Dipole moments of the diazines. |
Fig. 11 The two nitrogens of the pyridazines are capable to give interactions where the carbocycles do not give. |
The binding of the antirhinoviral agent R 61837 to human rhinovirus 14 has been examined by X-ray crystallographic methods.13 It appears clearly that the two COMPOUND LINKS
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Download mol file of compoundpyridazinenitrogens of the compound R 61837 establish two acceptor COMPOUND LINKS
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Download mol file of compoundhydrogen bonds with the receptorprotein (Fig. 12).
A pharmacophore model was derived from pdb structure 1R09 using LigandScout: red arrows represent H-bonds, yellow spheres hydrophobic areas of the ligand interacting with the protein.
Fig. 13 New isomeric azine-bridged dinuclear COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundplatinum(II) complexes circumvent cross-resistance to COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundcisplatin. |
Fig. 14 Replacement of the phenyl ring of COMPOUND LINKS Read more about this on ChemSpider Download mol file of compounddiazepam by the isosteric COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridazine ring produces an approximately two-unit decrease in the log P (calculated values). |
Similarly the bioisosteric change in compound 16 of a pyridine ring into a COMPOUND LINKS
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Download mol file of compoundpyridazine ring15 yielded improved COMPOUND LINKS
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Download mol file of compoundwater solubility (6 μg ml−1 instead of less than 0.5 μg ml−1) (Fig. 15).
Fig. 15 Replacement of the COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridine by a COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridazine improves the solubility in COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundwater. |
Fig. 16 The presence of a COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridazine ring in a bioactive molecule allows the preparation of solid, COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundwater-soluble salts. |
However, when a COMPOUND LINKS
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Download mol file of compoundpyridazine ring is present in a bioactive molecule, salt formation becomes possible, yielding colorless, COMPOUND LINKS
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Download mol file of compoundwater-soluble crystalline salts. Thus, for the compound 17, the hydrochloride solubility increases from 6 μg ml−1 to 120 mg ml−1.15
In the series of COMPOUND LINKS
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Download mol file of compounddiazine analogues of COMPOUND LINKS
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Download mol file of compoundridogrelCOMPOUND LINKS
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Download mol file of compound18, replacement of the 3-pyridyl group by a 2-pyrazinyl, 4-pyridazinyl or 5-pyrimidinyl moiety led to compounds that inhibit COMPOUND LINKS
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Download mol file of compoundthromboxane A2 synthetase and may serve as bioisosteric substitute of a 3-pyridyl group in antiplatelet agents (Fig. 17).16
Fig. 17 Replacement of the 3-pyridyl ring of COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundridogrel by 4-pyridazinyl ring yields highly potent anti-platelet agents. |
Starting from a COMPOUND LINKS
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Download mol file of compoundpyridineCOMPOUND LINKS
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Download mol file of compoundlead active as selective cannabinoid CB2agonist, Gleave et al.15 identified COMPOUND LINKS
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Download mol file of compoundpyridazine analogues with high potency in an in vivo model of inflammatory pain (Fig. 18).
Fig. 18 An essential step in optimization of the COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridine leadCOMPOUND LINKS Read more about this on ChemSpider Download mol file of compound20 was the replacement of the pyridine ring by a COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridazine. Additional modifications led to compound 21. |
Fig. 19 Bioisosteric replacement of a carboxamide by an COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundaminopyridazine. |
Attachment of a COMPOUND LINKS
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Download mol file of compoundbutyric acid chain to the endo-amidinonitrogen of a COMPOUND LINKS
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Download mol file of compound3-aminopyridazine yields “pyridazinyl-GABA's”, highly potent and selective antagonists of the GABA-A receptor (Fig. 20) and useful research tools for neuropharmacology.18,19 One of these compounds, Gabazine, is commercially available.
Fig. 20 Bioisosteric replacement of the COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundGABAamino function by an COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundaminopyridazine. |
As an example, when the initial hit contains a COMPOUND LINKS
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Download mol file of compoundpyridazine ring several bioisosteres can be considered a priori (Fig. 21): COMPOUND LINKS
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Download mol file of compoundpyridine, COMPOUND LINKS
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Download mol file of compoundpyrimidine, COMPOUND LINKS
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Download mol file of compoundpyrazine, 1,2,4-triazines, 3,4-oxadiazoles, 3,4-thiadiazoles, 2,4-oxadiazoles, 2,4-thiadiazoles and many others. We made the assumption that the boiling points of these heterocycles reflect their dipole moments and that the closest heterocycles in terms of boiling points are also the closest analogues in terms of pharmacological activity.
Fig. 21 Boiling points of COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundpyridazine bioisosteres. |
In COMPOUND LINKS
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Download mol file of compoundreserpine-induced ptosis and in 5-HT potentiation the three most potent compounds (in blue) are the COMPOUND LINKS
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Download mol file of compoundpyridazine, the COMPOUND LINKS
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Download mol file of compoundthiadiazole or the 1,2,4-diazine ring, all three characterized by boiling points close to 200 °C (Table 1). The less potent COMPOUND LINKS
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Download mol file of compoundpyrimidine and COMPOUND LINKS
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Download mol file of compoundpyrazine derivatives (in red) boil respectively at 123–124 and 115–118 °C. However, in the turning behavior test (values in black) no discrimination is found.
Fig. 22 Pyridazines as parts of fused bi- or tricyclic scaffolds. |
Picornaviruses cause numerous human diseases, including poliomyelitis, acute hepatitis, myocarditis and common cold. Compound 25 and congenate imidazo[1,2-b]pyridazines were found to be active against human picornaviruses.20
Pyrrolopyridazines 26 are novel acyl CoA:diacylglycerol acyltransferase (DGAT1) inhibitors.21 As DGAT1 catalyzes the esterification of 1,2-diacylglycerol with fatty acyl CoA to form triglycerides, their inhibition may be useful in lowering corporeal concentration and absorption of triglycerides.
Thienopyridazinones, as melanin-concentrating hormone 1 antagonists, are potent in vivo anorectic agents.22 In obese rats compound 27 demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg−1.
Pyrazolopyrimidopyridazinones 28 exhibit potent and selective phosphodiesterase 5 (PDE5) inhibitory activity.23 Compound 28 displays high potency (IC50 = 8.3 nM) with a high selectivity versusPDE6 (240-fold).
Fig. 23 A great variety of activity profiles derived from pyridazines scaffold. |
COMPOUND LINKS
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Download mol file of compoundMinaprine exhibits dopaminergic properties in vivo and the hydroxyl-ethylmetabolite CM 30094 combines sedative and anticonvulsant properties. Potent anticonvulsant properties were also found for compound SR 41378. Compound SR 95531, a combination of a 6-aryl-pyridazine and COMPOUND LINKS
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Download mol file of compoundGABA, turned out to be a potent and selective GABA-A receptor antagonist commercialized under the name Gabazine as a research tool for the neuropharmacologists. Exchanging the 4-methylgroup of COMPOUND LINKS
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Download mol file of compoundminaprine to a 4-cyanogroup yielded SR 95191 which in addition to the antidepressant properties is a potent monoamineoxidase A inhibitor. Further investigations on COMPOUND LINKS
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Download mol file of compoundminaprine analogues led to SR 46559A, a muscarinic M1 partial agonist, and to PCS 1055, a nanomolar acetylcholinesterase inhibitor.
Considering the various advantages of pyridazines in drug design: modulation of the physico-chemical properties, save ADME and toxicity profile, easy and diverse synthetic methods of access, reasonable unexplored medicinal chemistry routes, would be arguments enough to work with pyridazines.
But, even more, given their affinity for a great number of receptorproteinspyridazines can without doubt be considered as privileged structures. Therefore it becomes fully justified to include pyridazines in any drug candidate research program. For the same reason I recommend to make massive use of COMPOUND LINKS
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Download mol file of compoundpyridazine libraries in screening programs.
This journal is © The Royal Society of Chemistry 2011 |