2256 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Bebernitz et al.
(4) Molecular and Cellular Biology Unit, Novartis Institute for
Biomedical Research.
(22) Henderson, G. N.; Curry, S. H.; Derendorf, H.; Wright, E. C.;
Stacpoole, P. W. Pharmacokinetics of Dichloroacetate in Adult
Patients with Lactic Acidosis. J . Clin. Pharmacol. 1997, 37, 416-
425.
(23) Bersin, R.; Kwasman, M.; DeMarco, T.; Lau, D.; Klinski, C.;
Golonka, J .; Chatterjee, K. Improved Hemodynamic Function
in Congestive Heart Failure with the Metabolic Agent Sodium
Dichloroacetate (DCA). J . Am. Coll. Cardiol. 1990, 15, 157A.
(24) Dichloroacetic acid showed efficacy in these indications. For a
review of the pharmacology of DCA, see: Stacpoole, P. W. The
Pharmacology of Dichloroacetate. Metabolism 1989, 38, 1124-
1144.
(25) Aicher, T. D.; Anderson, R. C.; Bebernitz, G. R.; Coppola, G. M.;
J ewell, C. F.; Knorr, D. C.; Liu, C.; Sperbeck, D. M.; Brand, L.
J .; Strohschein, R. J .; Gao, J .; Vinluan, C. C.; Shetty, S. S.;
Dragland, C.; Kaplan, E. L.; DelGrande, D.; Islam. A.; Liu, X.;
Lozito, R. J .; Maniara, W.; Walter, R. E.; Mann, W. R. (R)-3,3,3-
Trifluoro-2-Hydroxy-2-Methylpropionamides are Orally Active
Inhibitors of Pyruvate Dehydrogenase Kinase. J . Med. Chem.,
1999, 42, 2741-2746.
(26) Aicher, T. D.; Damon, R. E.; Koletar, J .; Vinluan, C. C.; Brand,
L. J .; Gao, J .; Shetty, S. S.; Kaplan, E. L.; Mann; W. R.
Triterpene and Diterpene Inhibitors of Pyruvate Dehydrogenase
Kinase (PDHK). Biorg. Med. Chem. Lett. 1999, 9, 2223-2228.
(27) Aicher, T. D.; Anderson, R. C.; Gao, J .; Shetty, S.; Coppola, G.
M.; Stanton, J . L.; Knorr, D. C.; Sperbeck, D. M.; Brand, L. J .;
Vinluan, C. C.; Kaplan, E. L.; Dragland, C.; Tomaselli, H. C.;
Islam, A.; Lozito, R. J .; Liu, X.; Maniara, W. M.; Fillers, W. S.;
DelGrande, D.; Walter, R. E.; Mann, W. R. Secondary Amides
of (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic Acid as In-
hibitors of Pyruvate Dehydrogenase Kinase. J . Med. Chem. 2000,
43, 236-249.
(5) Caterson, I. D.; Kerby, A. L.; Cooney, G. J .; Frankland, R.;
Denyer, G. S.; Nicks, J .; Williams, P. F. Inactivation of Pyruvate
Dehydrogenase Complex in Heart Muscle Mitochondria of Gold-
Thioglucose-Induced Obese Mice is not Due to a Stable Increase
in Activity of Pyruvate Dehydrogenase Kinase. Biochem. J . 1988,
253, 291-294.
(6) (a) Wieland, O.; Siess, E.; Schulze-Wethmar, F. H.; von Funcke,
H. G.; Winton, B. Active and Inactive Forms of Pyruvate
Dehydrogenase in Rat Heart and Kidney: Effect of Diabetes,
Fasting, and Refeeding on Pyruvate Dehydrogenase Intercon-
version. Arch. Biochem. Biophys. 1971, 143, 593-601. (b) De-
nyer, G. S.; Lam, D.; Cooney, G. J .; Caterson, I. D. Effect of
Starvation and Insulin In Vivo on the Activity of the Pyruvate
Dehydrogenase Complex in Rat Skeletal Muscles. FEBS Lett.
1989, 250, 464-468. (c) Imura, M.; Takatani, O. Short-Term
Regulation of Pyruvate Dehydrogenase Complex by Insulin.
Horm. Metab. Res. 1981, 13, 267-272.
(7) Mondon, C. E.; J ones, I. R.; Azhar, S.; Hollenbeck, C. B.; Reaven,
G. M. Lactate Production and Pyruvate Dehydrogenase Activity
in Fat and Skeletal Muscle From Diabetic Rats. Diabetes 1992,
41, 1547-1554.
(8) Mandarino, L. J .; Consoli, A.; Kelly, D. E.; Reilly, J . J .; Nurjhan,
N. Fasting Hyperglycemia Normalizes Oxidative and Nonoxi-
dative Pathways of Insulin-Stimulated Glucose Metabolism in
Noninsulin-Dependent Diabetes Mellitus. J . Clin. Endocrinol.
Metab. 1990, 71, 1544-1551.
(9) Del Prato, S.; Bonadonna, R. C.; Bonora, E.; Gulli, G.; Solini,
A.; Shank, M.; DeFronzo, R. A. Characterization of Cellular
Defects of Insulin Action in Type 2 (Non-Insulin-Dependent)
Diabetes Mellitus. J . Clin. Invest. 1993, 91, 484-494.
(10) Henry, R. R.; Thorburn, A. W.; Beerdson, P.; Gumbiner, B. Dose-
Response Characteristics of Impaired Glucose Oxidation in Non-
Insulin-Dependent Diabetes Mellitus. Am. J . Physiol. 1991, 261,
E132-E140.
(11) Linn, T. C.; Pettit, F. H.; Reed, L. J . R-Keto Acid Dehydrogenase
Complexes. X. Regulation of the Activity of the Pyruvate
Dehydrogenase Complex from Beef Kidney Mitochondria by
Phosphorylation and Dephosphorylation. Proc. Natl. Acad. Sci.
USA 1969, 62, 234-241.
(28) Espinal, J .; Leesnitzer, T.; Hassman, A.; Beggs, M.; Cobb, J .
Inhibition of Pyruvate Dehydrogenase Kinase by Halogenated
Acetophenones. Drug Dev. Res. 1995, 35, 130-136.
(29) (a) Brieden, W.; Naughton, A.; Robins, K.; Shaw, N.; Tinshert,
A.; Zimmermann, T. Enzymic Method for the Stereoselective
Preparation of (S)- or (R)-3,3,3-trifluoro-2-hydroxy-2-methylpro-
pionic acids., Ger. Offen. (b) Konigsberger, K.; Prasad, K.; Repic,
O. The Synthesis of (R)- and (S)-R-Trifluoromethyl-R-hydroxy-
carboxylic Acids via enzymatic Resolutions. Tetrahedron Asym-
metry 1999, 10, 679-697.
(12) Sugden, P. H.; Kerbey, A. L.; Randle, P. J .; Waller, C. A.; Reid,
K. B. Amino Acid Sequences Around the Sites of Phosphorylation
in the Pig Heart Pyruvate Dehydrogenase Complex. Biochem.
J . 1979, 181, 419-426.
(13) Yeaman, S. J .; Hutcheson, E. T.; Roche, T. E.; Pettit, F. H.;
Brown, J . R.; Reed, L. J .; Watson, D. C.; Dixon, G. H. Sites of
Phosphorylation on Pyruvate Dehydrogenase from Bovine Kid-
ney and Heart. Biochemistry 1978, 17, 2364-2370.
(14) (a) Popov, K. M.; Kedishvili, N. Y.; Zhao, Y.; Shimomura, Y.;
Crabb, D. W.; Harris, R. A. Primary Structure of Pyruvate
Dehydrogenase Kinase Establishes a New Family of Eukaryotic
Protein Kinases. J . Biol. Chem. 1993, 268, 26602-26606. (b)
Popov, K. M.; Kedishvili, N. Y.; Zhao, Y.; Gudi, R.; Harris, R. A.
Molecular Cloning of the p45 Subunit of Pyruvate Dehydroge-
nase Kinase. J . Biol. Chem. 1994, 269, 29720-29724. (c) Gudi,
R.; Bowker-Kinley, M. M.; Kedishvili, N. A.; Zhao, Y.; Popov, K.
M. Diversity of the Pyruvate Dehydrogenase Kinase Gene
Family in Humans. J . Biol. Chem. 1995, 270, 28989-28994.
(15) Pratt, M. L.; Roche, T. E. Mechanism of Pyruvate Inhibition of
Kidney Pyruvate Dehydrogenasea Kinase and Synergistic Inhi-
bition by Pyruvate and ADP. J . Biol. Chem. 1979, 254, 7191-
7196.
(30) Morris, J . J .; Hughes, L. R.; Glen, A. T.; Taylor, P. J . Non-
Steroidal Antiandrogens. Design of Novel Compounds Based on
an Infrared Study of the Dominant Conformation and Hydrogen-
Bonding Properties of a Series of Anilide Antiandrogens. J . Med.
Chem. 1991, 34, 447-455.
(31) The acid chloride, if produced, does not acylate saturated primary
or cyclic secondary amines. The reaction may proceed through
a N-sulfinylamine intermediate, see: Shin, J . M.; Kim, Y. H.
New Facile Synthesis of R-Hydroxyamides: Intermolecular and
Intramolecular Catalysis in the Reaction of R-Hydroxycarboxylic
Acids with N-Sulfinylamines. Tetrahedron Lett. 1986, 27, 1971-
1974.
(32) (a) Schiess, M.; Seebach, D. N-Methyl-C-(trichlortitanio) From
Inimidoylchlorid. Ein Effizientes Reagenz zur Homologisierung
Von Aldehyden und Ketonen zu R-Hydroxy-Carbonsaureamiden.
Helv. Chim. Acta 1983, 66, 1618-1623. (b) Seebach, D.; Adam,
G.; Gees, T.; Schiess, M.; Weigand, W. Scope and Limitations of
the TiCl4-Mediated Additions of Isocyanides to Aldehydes and
Ketones with Formation of R-Hydroxycarboxylic Acid Amides.
Chem. Ber. 1988, 121, 507-517.
(33) Kelly, S. E.; LaCour, T. G. A One Pot Procedure For the
Synthesis of R-Hydroxyamides from the Corresponding R-Hy-
droxyacids. Synth. Commun. 1992, 22, 859-869.
(34) Nickson, T. E.; Roche-Dolson, C. A. A Convenient Procedure for
the Chlorination of Deactivated Anilines. Synthesis 1985, 669-
670.
(35) Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille, J . K.
Palladium-Catalyzed Coupling of 2-Bromoanilines with Vinyl-
stannanes. A Regiocontrolled Synthesis of Substituted Indoles.
J . Org. Chem. 1988, 53, 1170-1176.
(36) Blaney, F. E.; Clark, M. S. G.; Gardner, D. V.; Hadley, M. S.;
Middleton, D.; White, T. J . Anilides Related to Substituted
Benzamides. Potential Antipsychotic Activity of N-(4-Amino-5-
chloro-2-methoxyphenyl)-1-(phenylmethyl)-4-piperidinecarboxa-
mide. J . Med. Chem. 1983, 26, 1747-1752.
(16) Whitehouse, S.; Cooper, R. H.; Randle, P. J . Mechanism of
Activation of Pyruvate Dehydrogenase by Dichloroacetate and
other Halogenated Carboxylic Acids. Biochem J . 1974, 141, 761-
774.
(17) Stacpoole, P. W.; Moore, G. W.; Kornhauser, D. M. Metabolic
Effects of Dichloroacetate in Patients with Diabetes Mellitus and
Hyperlipoproteinemia. N. Engl. J . Med. 1978, 298, 526-530.
(18) (a) Curry, S. H.; Chu, P. I.; Baumgartner, T. G.; Stacpoole, P.
W. Plasma Concentrations and Metabolic Effects of Intravenous
Sodium Dichloroacetate. Clin. Pharmacol. Ther. 1985, 37, 89-
93. (b) Wells, P. G.; Moore, G. W.; Rabin, D.; Wilkinson, G. R.;
Oates, J . A.; Stacpoole, P. W. Metabolic Effects and Pharmaco-
kinetics of Intravenously Administered Dichloroacetate in Hu-
mans. Diabetologia 1980, 19, 109-113.
(19) Bersin, R. M.; Stacpoole, P. W. Dichloroacetate as Metabolic
Therapy for Myocardial Ischemia and Failure. Am. Heart J .
1997, 134, 841-855.
(20) Preiser, J . C.; Moulart, D.; Vincent, J . L. Dichloroacetate
Administration in the Treatment of Endotoxic Shock. Circ.
Shock. 1990, 36, 221-228.
(37) J ackson, J . C.; Vinluan, C. C.; Dragland, C. J .; Sundararajan,
V.; Yan, B.; Gounarides, J . S.; Nirmala, N. R.; Topiol, S.; Ramage,
P.; Blume, J . E.; Aicher, T. D.; Bell, P. A.; Mann, W. R.
Heterologously Expressed Inner Lipoyl Domain of Dihydrolipoyl
Acetyltransferase Inhibits ATP-Dependent Inactivation of Pyru-
vate Dehydrogenase Complex: Identification of Important Amino
Acid Residues. Biochem. J . 1998, 334, 703-711.
(38) Ohnmacht, C. J .; Russell, K.; Empfield, J . R.; Frank, C. A.;
Gibson, K. H.; Mayhugh, D. R.; McLaren, F. M.; Shapiro, H. S.;
Brown, F. J .; Trainor, D. A.; Ceccarelli, C.; Lin, M. M.; Masek,
B. B.; Forst, J . M.; Harris, R. J .; Hulsizer, J . M.; Lewis, J . J .;
(21) Granot, H.; Steiner, I. Successful Treatment of Irreversible
Hemorragic Shock in Dogs with Fructose-1,6-Diphosphate and
Dichloroacetate. Circ. Shock 1985, 15, 163-173.