Fab I inhibitors

Details Fab I inhibitors Fab I inhibitors

2002-11-12

2004-07-20

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S510000

Reexamination Certificate

active

06765005

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pharmaceutically active compounds which inhibit Fab I and are useful for the treatment of bacterial infections.
BACKGROUND OF THE INVENTION
While the overall pathway of saturated fatty acid biosynthesis is similar in all organisms, the fatty acid synthase (FAS) systems vary considerably with respect to their structural organization. Vertebrates and yeast possess a FAS in which all the enzymatic activities are encoded on one or two polypeptide chains, respectively, and the acyl carrier protein (ACP) is an integral part of the complex. In contrast, in bacterial FAS, each of the reactions is catalyzed by a distinct, mono-functional enzyme and the ACP is a discrete protein. Therefore, there is considerable potential for the selective inhibition of the bacterial system by antibacterial agents.
Fab I (previously designated EnvM) functions as an enoyl-ACP reductase (Bergler, et al, (1994),
J. Biol. Chem.
269, 5493-5496) in the final step of the four reactions involved in each cycle of bacterial fatty acid biosynthesis. In this pathway, the first step is catalyzed by &bgr;-ketoacyl-ACP synthase, which condenses malonyl-ACP with acetyl-CoA (FabH, synthase III). In subsequent rounds, malonyl-ACP is condensed with the growing-chain acyl-ACP (FabB and FabF, synthases I and II, respectively). The second step in the elongation cycle is ketoester reduction by NADPH-dependent &bgr;-ketoacyl-ACP reductase (FabG). Subsequent dehydration by &bgr;-hydroxyacyl-ACP dehydrase (either FabA or FabZ) leads to trans-2-enoyl-ACP, which in turn is converted to acyl-ACP by NADH-dependent enoyl-ACP reductase (Fab I). Further rounds of this cycle, adding two carbon atoms per cycle, eventually lead to palmitoyl-ACP (16C), where upon the cycle is stopped largely due to feedback inhibition of Fab I by palmitoyl-ACP (Heath, et al, (1996),
J. Biol. Chem.
271, 1833-1836). Thus, Fab I is a major biosynthetic enzyme and is a key regulatory point in the overall synthetic pathway of bacterial fatty acid biosynthesis. Therefore, Fab I is an ideal target for antibacterial intervention.
Studies have shown that diazaborine antibiotics inhibit fatty acid, phospholipid and lipopolysaccharide (LPS) biosynthesis and that the antibacterial target of these compounds is Fab I. For example, derivative 2b18 from Grassberger, et al (1984)
J. Med Chem
27 947-953 has been reported to be a non-competitive inhibitor of Fab I (Bergler, et al, (1994),
J. Biol. Chem.
269, 5493-5496). Also, plasmids containing the Fab I gene from diazaborine resistant
S. typhimurium
conferred diazaborine resistance in
E. coli
(Turnowsky, et al, (1989),
J. Bacteriol.,
171, 6555-6565). Furthermore, inhibition of Fab I either by diazaborine or by raising the temperature in a Fab I temperature sensitive mutant is lethal. These results demonstrate that Fab I is essential to the survival of the organism (Bergier, et al, (1994),
J. Biol. Chem.
269, 5493-5496).
Recent studies have shown that Fab I is also the target for the broad spectrum antibacterial agent triclosan (McMurry, et al, (1998)
Nature
394, 531-532). A crystal structure of the
E. Coli
Fab I complexed with NAD and triclosan shows that triclosan acts as a site-directed, very potent inhibitor of Fab I by mimicking its natural substrate (Levy, et al, (1999)
Nature
398, 383-384). Ward, et al ((1999)
Biochem.
38, 12514-12525) have shown that there is no evidence for the formation of a covalent complex between Fab I and triclosan, which would be analogous to the diazaborines; triclosan differs from these compounds in that it is a reversible inhibitor of Fab I. The structural data for the complex of Fab I with NAD and triclosan provides important information about Fab I as a therapeutic target.
Importantly, it has now been discovered that certain compounds are Fab I inhibitors and have antibacterial activity, and, therefore, may be useful for the treatment of bacterial infections in mammals, particularly in man.
SUMMARY OF THE INVENTION
This invention comprises compounds of the formula (I), as described hereinafter, which inhibit Fab I and are useful in the treatment of bacterial infections.
This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
This invention is also a method of treating bacterial infections by inhibiting Fab I. In a particular aspect, the compounds of this invention are useful as antibacterial agents.


REFERENCES:
patent: 3828068 (1974-08-01), Minieri
patent: 4154943 (1979-05-01), Kuehne
patent: 4977159 (1990-12-01), Sevrin et al.
patent: 5614551 (1997-03-01), Dick et al.
patent: 5624941 (1997-04-01), Barth et al.
patent: 5932743 (1999-08-01), Collini et al.
patent: 5985867 (1999-11-01), Rodgers et al.
patent: 6346391 (2002-02-01), Oethinger et al.
patent: 6372752 (2002-04-01), Staveski et al.
patent: 6451816 (2002-09-01), Biedermann et al.
patent: 6469046 (2002-10-01), Daines et al.
patent: 6503903 (2003-01-01), Miller et al.
patent: 6503908 (2003-01-01), Maw
patent: 6559172 (2003-05-01), Heerding et al.
patent: 6573272 (2003-06-01), Miller et al.
patent: WO 95/18619 (1995-07-01), None
patent: WO 96/00730 (1996-01-01), None
patent: WO 97/48696 (1997-12-01), None
patent: WO 98/57952 (1998-12-01), None
patent: WO 01/26652 (2001-04-01), None
patent: WO 01/26654 (2001-04-01), None
patent: WO 01/27103 (2001-04-01), None
patent: WO 01/48248 (2001-07-01), None
patent: WO 02/42273 (2002-05-01), None
patent: WO 02/48097 (2002-06-01), None
Abou-Gharbia et al., “Psychotropic Agents: Synthesis and Antipysychotic Activity of Substituted B-Carbolines,” J. Med. Chem., 30(6): 1100-1115 (1987).
Ahsan et al., “Reserpine Anlogues: Synthesis of B-Carboline Derivatives,” J. Chem. Soc., pp. 3928-3920 (1963).
Database Crossfire Beilstein, 1966, Database accession No. 2819049, 2819050, XP002216033.
Database CA on STN, AN 7:66733, Rosenmund et al., “Chemistry of indole II . . . ,”Chem Ber. 103(2): 496-509 (1970).
Database CAOLD on STD, AN CA51:10524d, Hellman et al., “N-Mannich bases (VI) condensation . . . ,”Direct Submission(1953).
Database CAPLUS on STN, An 1977:439214. Misztal et al., “Synthesis and pharmacologic properties of pyridoyl . . . ,”Arch Immuno Ther Exp. 24(6): 851-862 (1976).
Himmer et al., “Synthesis and Antibacterial in Vitro Activity of Novel Analogues of Nematophin,” Bioorganic & Medicinal Chemistry Letters, 8(15): 2045-2050 (Aug. 1998).
Jianxiong et al., “Synthesis and Antistaphylococcal Activity of Nematophin and Its Analogs,” Bioorganic & Medicinal Chemistry Letters, Oxford, GB, 7(10): 1349-1352, (May 20, 1977) XP004136332.
Miller et al., Discovery of Aminopyridine-Based Inhibitors of Bacterial Enoyl-ACP Reductase (FABI); J. Med. Chem. 2002, vol. 45, pp. 3246-3256.
Misztal et al., “Synthesis and Pharmacologic Properties of Pyridol Derivatives of 3-Methylaminoindole 2-Methyltryptamine and Isotryptamine,” Archivum Immnologiae et Therapiae Experimentalis, 24(6): 851-852 (1976).
Pachter et al., “The Chemistry of Hortiamine and 6-Methoxyhetsinine,” J. Amer. Chem., 83:635-642 (1961).
Rehse et al., “Dopaminanaloge 1,2,3,4-Tetrahydro-B-Carboline,” Arch. Pharm., 311(1):11-18 (1978).
Shoji et al., “Two Novel Alkaloids from Evodia Rutaecarpa,” J. Natural Products, 52(5):1160-1162 (1989).

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