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Definitions

• the invention relates to novel compounds that stimulate rates of glucose oxidation in myocardial cells.
• the invention also relates to pharmaceutical compositions comprising compounds capable of stimulating glucose oxidation, methods for increasing glucose oxidation rates in myocardial cells, and methods of treatment of myocardial ischemia.
• Myocardial ischemia is a common clinical pathology that occurs in the setting of angina pectoris, acute myocardial infarction, or during cardiac surgery. Myocardial ischemia is a major clinical problem, with its complications being the major cause of mortality and morbidity in Western society.
• the heart To meet the high energy demands of the contracting muscle, the heart must produce a constant and pl-entiful supply of the free energy carrier, adenosine triphosphate (ATP) .
• ATP adenosine triphosphate
• This energy is produced by the metabolism of a variety of carbon substrates, including carbohydrates such as glucose.
• the metabolism of fatty acid is the other major source of energy for the heart.
• Glucose metabolism in the heart consists of two important pathways, namely glycolysis and glucose oxidation. It has been shown that during ischemia (such as that produced by angina pectoris, myocardial infarction or heart surgery) the levels of circulating fatty acids in the plasma can be dramatically elevated. Am Heart J 128: -61-7, 1994. As a result, during ischemia and reperfusion the heart is exposed to high levels of fatty acids, which results in the preferential use of fatty acids as an oxidative substrate over glucose. It further has been reported that this over- reliance on fatty acids as a major source of ATP contributes to fatty acid-induced ischemic damage.
• Trimetazidine is reported to primarily act by inhibiting fatty acid oxidation, thereby stimulating glucose oxidation in the heart.
• a second clinically effective agent that is reported to switch energy metabolism from fatty acid to glucose oxidation is ranolazine. It has been reported that this agent stimulates glucose oxidation secondary to an inhibition of fatty acid oxidation Circulation 93: 135-42., 1996.
• the detrimental effects of fatty acids on mechanical function during and following ischemia may also be attenuated by agents that increase glucose oxidation directly.
• Numerous experimental studies have reported that stimulation of glucose oxidation by using dichloroacetate (DCA) following ischemia (at the expense of fatty acids) can benefit the ischemic heart. Am Heart J 134: 841-55, 1997.
• DCA dichloroacetate
• DCA is an effective compound designed to stimulate glucose oxidation, it has a short biological half-life. Therefore, there is need to develop novel class of compounds and to identify compounds that can stimulate glucose oxidation, have long biological life, and be effective in treatment or prevention of myocardial ischemia
• the present invention is directed to novel compounds represented by Formula (I) :
• W is Ci-C ⁇ alkyl, halogen, optionally substituted aryl, optionally substituted aralkyl or optionally substituted aralkenyl;
• Cyc is C3 or C 4 cycloalkyl
• (c) p is an integer from 0 to 4.
• Y is 0, S, or NR;
• f if m is 1 and if p is 0, Y is. O, and n is not 0, then Z is (cyclo) alkycarbonyl or if m is 1 and if p is O, Y is 0 and n is 0, then Z is heterocycle alkyl;
• X is 0, S, NR, or CR 3 R 4 ;
• R is H, alkyl, aryl, or
• i is an integer from 2 to 4.
• Z is H, alkyl, heterocycle alkyl, cycloalkyl, aryl or optionally substituted Ci-C ⁇ alkylcarbonyl or
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; or when X is CR 3 R 4 then R 3 and R 4 , taken together with the carbon atom, may form a heterocyclic ring; and
• n is an integer from 1 to 10; or a -pharmaceutically acceptable salt, ester or prodrug thereof.
• the present invention is directed to novel compounds which are represented by Formula (IIS) : (Formula IIS)
• W is Ci-C ⁇ alkyl, halogen, optionally substituted aryl, optionally substituted aralkyl or optionally substituted aralkenyl;
• Cyc is C3 or C 4 cycloalkyl; and
• p is an integer from 1 to 4, -or a pharmaceutically acceptable salt, ester or prodrug thereof. While not wishing to be bound by any particular mechanism of action, it is believed that compounds of Formula (IIS) are esterfied with CoA in vivo.
• novel compounds are provided which are represented by Formula (Ilia) :
• W is Ci-C ⁇ alkyl, halogen, or aryl; Cyc is C 3 or C 4 cycloalkyl; p is an integer from 0 to 3 when Cyc is C 4 cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3 cycloalkyl;
• i is an integer from 2 to 4;
• Z is H, alkyl, cycloalkyl, aryl or (cyclo) alkylcarbonyl
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• novel compounds represented by Formula (Ilib) :
• W is Ci-C 6 alkyl, halogen, or aryl; Cyc is C 3 or C 4 cycloalkyl; p is an integer from 0 to 3 when Cyc is C 4 cycloalkyl, or p is an integer from 0 to 2 when Cyc is C3 cycloalkyl; Y is NR;
• X is 0, S, NR, or CR 3 R 4 ;
• R is H, alkyl or aryl;
• Z is H, alkyl, cycloalkyl, aryl or (cyclo) alkylcarbonyl;
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• novel compounds represented by Formula (IIIc) are novel compounds represented by Formula (IIIc) :
• W is Ci-C ⁇ alkyl, halogen, or aryl; Cyc is C3 or C 4 cycloalkyl; p is an integer from 0 to 3 when Cyc is C 4 cycloalkyl, or p is an integer from 0 to 2 when Cyc is C3 cycloalkyl; Y is 0, S, or NR;
• Z is (cyclo) alkylcarbonyl or
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• W is Ci-C ⁇ alkyl, halogen or aryl; Cyc is C 3 or C 4 cycloalkyl; p is an interger for 0 to 3 when Cyc is C 4 cycloalkyl or p is an interger from 0 to 2 when Cyc is C 3 cycloalkyl;; Y is 0; X is NR;
• R is H, alkyl, aryl, or
• i is an integer from 2 to 4.
• Z is H, alkyl, cycloalkyl, aryl or (cyclo) alkylcarbonyl
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• W is aryl
• Cyc is C 3 or C 4 cycloalkyl
• Y is 0, S, or NR
• X is 0, S, NR, or CR 3 R 4 ;
• R is H, alkyl, aryl, or
• i is an integer from 2 to 4.
• Z is H, alkyl, cycloalkyl, aryl or (cyclo) alkylcarbonyl or
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• the present invention is further directed to methods for increasing or improving glucose utilization in myocardial or other types of cells, tissue or organs of warm blooded animals, especially those which are capable of high glucose metabolism (e.g., heart and other muscles) .
• the method comprises treating cells, tissue or organs with substituted or unsubstituted cyclopropane carboxylic acid or cyclobutane carbothioi-c a-cid represented by the Formula (IIS) :
• the present invention is also directed to pharmaceutical compositions comprising a compound according to Formula (IIS) , Formula (I) or any of Formulas (Ilia) to (I ⁇ Ie)and suitable pharmaceutical carriers, excipients or fillers.
• the present invention is directed to a method of treating physiological conditions or disorders that may be effectively treated by increasing of cell glucose utilization.
• such method comprises administering to a patient in need of such treatment an effective amount of a pharmaceutical composition comprising substituted or unsubstituted cyclopropane carboxylic acid or cyclobutane carbothioic acid according to Formula (IIS) or a cyclopropane carboxylic acid or cyclobutane carboxylic acid derivative of Formula (I) and any of Formulas (Ilia) to (HIe) .
• a pharmaceutical composition comprising substituted or unsubstituted cyclopropane carboxylic acid or cyclobutane carbothioic acid according to Formula (IIS) or a cyclopropane carboxylic acid or cyclobutane carboxylic acid derivative of Formula (I) and any of Formulas (Ilia) to (HIe) .
• the present invention is further directed to kits including a pharmaceutical composition according to the • present invention.
• the methods of the present invention are applicable for treating warm blooded animal subjects, such as mammals, including humans, primates, etc.
• alkenyl refers to unsaturated aliphatic groups having at least one double bond.
• alkyl refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic (including cycloalkyl and polycyclic alkyl) groups.
• alkoxy and alkoxyl refer to a group having the formula, R-O-, wherein R is an alkyl gr-oup.
• alkoxycarbonyl refers to -C(O)OR wherein R is alkyl.
• alkenyl refers to an alkenyl group substituted with an aryl group.
• alkenyl group has from 2 to about 6 carbon atoms.
• aralkyl refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, phenethyl, and the like, all of which may b.e optionally substituted. Preferably the alkyl group has from 1 to about 6 carbon atoms.
• aryl refers to an aromatic ⁇ group- whi-ch has at least one ring having a conjugated pi electron system and includes a carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
• aryloxy refers to a group having the ⁇ formula, R-O-, wherein R is an aryl group.
• aralkoxy refers to a group having the formula, R-O-, wherein R is an aralkyl group.
• Biaryl refers to phenyl substituted by carbocyclic or heterocyclic aryl as defined herein, ortho, meta or para to the point of attachment of th-e phenyl ring.
• Bosset refers to an aqueous saturated solution of sodium chloride.
• Carbocyclic aryl refers to aromatic groups wherein the ring atoms on the aromatic ring are carbon atoms.
• Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and naphthyl groups, all of which may be optionally substituted.
• Suitable carbocyclic aryl groups include phenyl and naphthyl .
• Suitable substituted carbocyclic aryl groups include indene and phenyl substituted by one to two substituents such being advantageously lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, halogen, trifluoromethyl, difluoromethyl, nitro, and cyano.
• Substituted naphthyl refers to naphthyl, more preferably -1- or 2-naphthyl, substituted by Yl, Y2 and/or Y3 as defined in connection with formula (I) hereinabove.
• Cycloalkenyl refers to a cyclic alkenyl' group. Suitable cycloalkenyl groups include, for example, cyclopentenyl and cyclohexenyl.
• Cycloalkyl refers to a cyclic alkyl group having at least one ring and includes polycyclic groups, including fused ring cyclic alkyl groups and bridged cycloalkyl groups. Suitable cycloalkyl groups include, for example, cyclohexyl, cyclopropyl, cy-clopentyl, cycloheptyl and adamantyl . "Cyclohaxylmethyl” refers to. a cyclohexyl group attached to CH 2 .
• Diol refers to chemical species having at least two hydroxy (-0H) functional groups. Diols may contain more than two hydroxy groups. "Vicinal diols” are those in which two hydroxy groups are on adjacent carbons, as found for -example in pinanediol. "Fused carbocyclic” refers to a multicyclic fused carbocyclic ring having both aromatic and non-aromatic rings. Suitable fused carbocyclic rings include fluorenyl, tetralin and the like.
• fused carbocyclic alkyl refers to an alkyl group substituted with a fused carbocyclic ring moiety, preferably a multicyclic fused carbocyclic ring including both aromatic and non-aromatic rings. Suitable fused carbocyclic alkyl groups include fluorenylmethyl, and the like.
• halogen refers to fluorine, chlorine, bromine and iodine.
• Heteroaralkenyl refers to an alkenyl group substituted with a heteroaryl, and includes those heterocyclic systems described in "Handbook of Chemistry and Physics", 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, OH. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems.
• the alkenyl group has from 2 to about 6 carbon atoms.
• Heteroaralkyl refers to an alkyl group substituted with a heteroaryl, such as picolyl, ⁇ and includes those heterocyclic systems described in "Handbook of Chemistry and Physics", 49th edition, 1968, R. C. Weast, editor; The ⁇ • Chemical Rubber Co., Cleveland, OH. See particularly Section C, Rules for Naming Organic Compounds, B.
• the alkyl group has from 1 to about 6 carbon atoms .
• Heteroaryl refers to aromatic groups having from 1 to 14 carbon atoms and the remainder of the ring atoms are heteroatoms, and includes those heterocyclic systems described in "Handbook of Chemistry and Physics", 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, OH. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems.
• Suitable heteroatoms include oxygen, nitrogen, and S(0)i, wherein i is 0, 1 or 2
• suitable heterocyclic aryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like.
• Heterocycle or “Heterocyclic” refers to both heteroaryl and hetercyclo groups.
• Heterocycle alkyl refers to an alkyl group substituted with a heterocycle group.
• Heterocyclicoxy refers to the group -OR where R is a heterocycle group.
• Heterocyclo refers to a reduced heterocyclic ring system comprised of carbon, nitrogen, oxygen and/or sulfur atoms, and includes those heterocyclic systems described in "Handbook of Chemistry and Physics", 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, OH. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems.
• Heterocycloalkyl refers to an alkyl group substituted with a heterocyclo group, and includes those heterocyclic systems described in "Handbook of Chemistry and Physics", 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, OH. See particularly Se-ction C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems.
• the alkyl group has from about 1 to about 6 carbon atoms.
• radicals or groups with one and up to and including 5 carbon atoms, preferably up to and including 4 carbon atoms, and advantageously one or two carbon atoms.
• Such radicals or groups may be straight chain or branched chain.
• “Pharmaceutically acceptable salt” includes salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid. In practice the use of the salt form amounts to use of the base form. The compounds of the ' present invention are useful in both free base and salt form, with -both forms being considered as being within the scope of the present invention.
• Figure 1 is a graph which depicts glucose oxidation in an isolated perfused working rat heart model at the indicated concentrations of cyclopropanecarboxylic acid, 2- [2- (2- methoxy-ethoxy) -ethoxy] -ethyl ester (MM054) as compared to a control.
• Figure 2 is a graph which depicts glucose oxidation in an isolated perfused working rat heart model at the indicated concentrations of cyclobutanecarboxylic acid, 2- [2- (2-methoxy-ethoxy) -ethoxy] -ethyl -ester (MM056) as compared to a control .
• Figure 3 is a graph which depicts glucose oxidation in an isolated perfused working rat heart model at increasing concentrations of cyclopropanecarboxylic acid, 2-isopropoxy- ethyl ester (MM070) as compared to a control.
• Figure 4 is a graph which depicts glucose, -oxidation in an isolated perfused working rat heart model at increasing concentrations of cyclopropanecarboxylic acid (MMOOl) as compared to a control.
• MMOOl cyclopropanecarboxylic acid
• Figure 5 is a graph which depicts glucose oxidation in an isolated perfused working heart model at the indicated concentrations of dichloroacetate (DCA) , Compound 15 (MM068), Compound 41 (MM094) and Compound 45 (MM098), compared to a control .
• DCA dichloroacetate
• MM068 Compound 15
• MM094 Compound 41
• MM098 Compound 45
• Figure 6 is a graph which depicts glucose oxidation in an isolated perfused rat heart model at the indicated concentrations of DCA, cyclopropanecarboxylic acid ⁇ MM001) and cyclobutanecarboxylic acid (MM013) as compared to a control.
• Figure 7 is a graph which depicts glucose oxidation in an isolated perfused rat heart model for concentrations of cyclopropanecarboxylic acid (MMOOl) as compared with a control.
• MMOOl cyclopropanecarboxylic acid
• Figure 8 is a graph which depicts glucose oxidation in an isolated perfused rat heart model for increasing concentrations of cyclobutanecarboxylic acid (MM013) a-s compared to a control.
• Figure 9 is a graph which depicts Pyruvate Dehydrogenase Kinase (PDHK) activity at ImM of DCA or cyclopropanecarboxylic acid (MMOOl) as a percent of a control, using the PDHK assay described in Example C.
• Figure 10 is a graph which depicts PDHK activity at ImM of DCA, cyclopropanecarboxylic acid (MMOOl) or the CoA ester of cyclopropanecarboxylic acid (MM053) as a percent of a control, using the PDHK assay described in Example C.
• Figure 11 depicts a schematic for a mechanism of intracellular activation of cyclopropanecarboxylic aci-d (MMOOl) to give the corresponding CoA ester (MM053) .
• the present invention is directed to the use of certain compounds in methods of treatment which increase glucose utilization and which ameliorate conditions which would benefit from increased glucose utilization. Included are methods for increasing glucose utilization in a cell, tissue, or organ of a warm blooded animal comprising treating said cell, tissue or organ with a glucose utilization increasing effective amount of at least one compound represented by the formulas set forth herein. Also included are methods for treatment of physiological conditions or disorders treatable by increasing glucose utilization comprising administering to a patient in need of such treatment, an effective amount to increase glucose utilization of a pharmaceutical composition comprising at least one compound as described herein. Such compounds include the compounds represented by Formulas (I), (IIS), III and (Ilia) to (HIe) .
• MMOOl is cyclopropanecarboxylic acid, which we had identified as a stimulator of glucose oxidation in the heart.
• MM013 is a compound that we demonstrated to stimulate glucose oxidation.
• Concentration curves for MMOOl and MM013 are shown in Figure 7 and Figure 8, respectively.
• MMOOl glucose oxidation stimulating activity
• PDHK activity was measured as described in Example C: Our initial results demonstrated that the compound tested did not directly inhibit PDHK in vitro. However, we had evidence to prove that PDHK activity in ex vivo hearts was inhibited ( Figure 9) .
• the compounds described herein act by a prodrug mechanism in inhibiting PDHK, that is, when administered in vivo the compound undergoes an intracellular modification to produce a product that inhibits PDHK. (See Figure 11)
• the compounds described herein act as prodrugs.
• MM053 When tested in the in vitro PDHK assay, MM053 was active and did inhibit PDHK activity.
• MM053 appears to be an active . form of the compound (MMOOl) that inhibits PDHK directly (See Figure 10) . It is believed that the compounds described herein that stimulate glucose oxidation may be similarly modified in vivo and may be prodrugs of the corresponding CoA esters .
• compounds of the Formula (III) which are active in stimulating glucose oxidation are provided.
• the compounds represented by Formula (III) are:
• W is Ci-Ce alkyl, halogen, or aryl
• Cyc is C 3 or C 4 cycloalkyl; p is an integer from 0 to 3 when Cyc is G 4 cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3 cycloalkyl.;.,
• Y is 0, S, or NR
• X. is 0, S, NR, or CR 3 R 4 ,.
• Z is H, alkyl, cycloalkyl, aryl or (cyclo) alkylcarbonyl or
• R is H, alkyl, aryl or
• i is an integer from 2 to 4.
• R 1 is H, alkyl, or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• the present invention provides novel compounds which are derivatives of a cyclopropane carboxylic acid or a cyclobutane carboxylic acid. These compounds exhibit glucose oxidation stimulating activity in myocardial cells and other types of cells.
• the compounds according to the present invention are represented by the Formula (I) :
• W is Ci-C 6 alkyl, halogen, optionally substituted aryl, optionally substituted aralkyl or optionally substituted aralkenyl;
• Cyc is C 3 or C 4 cycloalkyl
• (c) p is an integer from 0 to 4.
• i is an integer from 2 to 4.
• Z is H, alkyl, heterocycle alkyl, cycloalkyl, aryl or optionally substituted Ci-C ⁇ alkylcarbonyl or
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; or when X is CR 3 R 4 then R 3 and R 4 , taken together with the carbon atom, may form a heterocyclic ring; and (m) n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• the present invention provides novel compounds according to the present invention which are represented by Formula (HS)- : • ⁇
• novel compounds are provided which are represented by Formula (Ilia) :
• W is Ci-C ⁇ alkyl, halogen, or aryl; Cyc is C 3 or C 4 cycloalkyl; p is an integer from 0 to 3 when Cyc is C 4 cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3 cycloalkyl;
• i is an integer from 2 to 4.
• Z is H, alkyl, cycloalkyl, aryl or (cyclo) alkylcarbonyl
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• novel compounds represented by Formula (HIb) are.. novel compounds represented by Formula (HIb) :
• W is Ci-C ⁇ alkyl, halogen, or aryl
• Cyc is C3 or C4 cycloalkyl; p is an integer from 0 to 3 when Cyc is C 4 cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3 cycloalkyl;
• Y is NR
• X is 0, S, NR, or CR 3 R 4 ;
• R is H, alkyl or aryl
• Z is H, alkyl, cycloalkyl, aryl or (cyclo) alkylcarbonyl;
• R 1 is H, alkyl or aryl; .
• R 3 and R 4 are, independently, H, alkyl or aryl; and. n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• novel compounds represented by Formula (IIIc) are novel compounds represented by Formula (IIIc) :
• W is Ci-C ⁇ alkyl, halogen, or aryl; Cyc is C3 or C 4 cycloalkyl; p is an integer from 0 to 3 when Cyc is C 4 cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3 cycloalkyl; Y is O, S, or NR;
• Z is (cyclo) alkylcarbonyl or
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• W is Ci-C ⁇ alkyl, halogen or aryl; Cyc is C 3 or C 4 cycloalkyl; p is an interger for 0 to 3 when Cyc is C 4 cycloalkyl or p is an interger from 0 to 2 when Cyc is C 3 cycloalkyl;; Y is 0; X is NR;
• R is H, alkyl, aryl, or
• i is an integer from 2 to 4.
• Z is H, alkyl, cycloalkyl, aryl or (cyclo) alkylcarbonyl or
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• W is aryl
• Cyc is C 3 or C 4 cycloalkyl; p is 1;
• Y is 0, S, or NR
• X is 0, S, NR, or CR 3 R 4 ;
• R is H, alkyl, aryl, or
• i is an integer from 2 to 4.
• Z is H, alkyl, cycloalkyl, aryl or (cyclo) alkylcarbonyl or
• R 1 is H, alkyl or aryl
• R 3 and R 4 are, independently, H, alkyl or aryl; and n is an integer from 1 to 1-0; or a .pharmaceutically acceptable salt, ester or prodrug thereof.
• Certain compounds according to the present invention may be conveniently prepared from the appropriate substituted or unsubstituted cyclopropane carbonyl chloride or cyclobutane carbonyl chloride according to the following reaction scheme:
• R 1 , R 2 , X, and n are as defined in connection with Formula (I) and Z is H, alkyl (including cycloalkyl) , aryl or alkycarbonyl.
• Other compounds of Formula (I) and of Formulas (Ilia) to (HIe) may be prepared by methods similar to those described in Examples 1 to 27 and using the appropriate starting materials.
• Suitable solvents include inert organic solvents such as dichloromethane and suitable base catalysts include triethylamine and pyridine.
• Reaction conditions may be varied depending on the starting materials and the desired end product.
• the invention further provides a method for increasing:; the rate of glucose oxidation and improving glucose utilization in myocardial and other cells, tissue or organs of humans and animals. It has been discovered that certain substituted cyclopropanecarbothioic acid and cyclobutanecarbothioic acid derivatives and certain substituted or unsubstituted cyclopropanecarboxylic acid and cyclobutanecarboxylic acid derivatives represented by
• Formula (IIS) by Formula (I) and any of Formula -(HIa) to (HIe) can increase glucose utilization in myocardial an other types of cells, tissue or organs of warm blooded animals, including humans.
• Compounds of Formula (IIS) have the structure:
• W is Ci-C 6 alkyl, halogen, optionally substituted aryl, optionally substituted aralkyl or optionally substituted aralkenyl; Cyc is C 3 or C 4 cycloalkyl; and p is an integer from 1 to 4; or a pharmaceutically acceptable salt, ester ' or prodrug thereof. . . ⁇ .
• the method according to the present invention comprises treating cells, tissue or organs of an animal with at least one compound represented by Formula (I) , any of Formulas (Ilia) to (HIe) or Formula (IIS) in an amount effective to stimulate glucose utilization.
• the compounds of Formula (I) , Formulas (Ilia) to (HIe) or Formula (IIS) may be delivered to the cells, tissues or organs by conventional means of administrating pharmaceutical compositions such as oral administration, injection or infusion, etc., of the compounds of the Formula.. (I), Formulas (Ilia) to (HIe) or (IIS), to the animal.
• the invention further provides pharmaceutical compositions comprising, as its active component, at least one compound according to the Formulas (I), (Ilia) to (HIe) or (IIS) or their pharmaceutically acceptable salts, esters or prodrugs.
• Pharmaceutical compositions comprising more than one compound according to the Formulas (I) , (Ilia) to
• compositions or formulations include compositions and formulations conventionally used in the pharmaceutical arts and may comprise carriers and excipients compatible with oral, intravenous, intramuscular, intraarterial, intracranial, and/or intracavity administration. Suitable pharmaceutical compositions and/or formulations may further compose colloidal dispersion systems, or lipid formulations (e.g., cationic or anionic lipids), micelles, microbeads, etc.
• colloidal dispersion systems or lipid formulations (e.g., cationic or anionic lipids), micelles, microbeads, etc.
• compositions of the present invention may comprise pharmaceutically acceptable and physiologically acceptable carriers, diluents or excipients.
• suitable carriers, diluents and excipients include solvents (aqueous or non-aqueous) , solutions, emulsions, dispersion media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration, and other commonly used carriers known in the art.
• compositions may also ' include carriers to protect the composition against rapid degradation or elimination from the body, and, thus may comprise a controlled release formulation, including implants and microencapsulated delivery systems.
• a time delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed.
• Pharmaceutical compositions can be formulated to be • compatible with a particular route of administration.
• a composition can be incorporated with excipients and used in the form of tablets, pills or capsules, e.g., gelatin capsules.
• Pharmaceutically compatible binding agents, and/or adjuvant materials can be included in oral formulations.
• the tablets, pills, capsules, etc. can contain any of the following- ingredients, or similar compounds: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating a-gent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; or a flavoring or sweetening agent .
• a binder such as microcrystalline cellulose, gum tragacanth or gelatin
• an excipient such as starch or lactose, a disintegrating a-gent such as alginic acid, Primogel, or corn starch
• a lubricant such as magnesium stearate or Sterotes
• a glidant such as colloidal silicon dioxide
• a flavoring or sweetening agent a flavoring or sweetening agent
• compositions for parenteral, intradermal, or subcutaneous administration can include a sterile diluent, such as water, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
• a sterile diluent such as water, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
• antibacterial agents such as benzyl alcohol or methyl parabens
• antioxidants such as ascorbic acid or sodium bisulfite
• chelating agents such as ethylenediaminetetraacetic acid
• compositions for injection include sterile aqueous solutions (where water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
• suitable -carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS) .
• Antibacterial and antifungal agents include, for example, parabens, chlorobutanol, phenol, ascorbic acid and ' thimerosal.
• Isotonic agents for example, sugars, polyalcohols such ' as manitol, sorbitol, sodium chl ⁇ -fide ' may be included in the composition.
• Including an agent which delays absorption, for example, aluminum monostearate and gelatin can prolong absorption of injectable compositions.
• the pharmaceutical formulations can be packaged in dosage unit form for ease of administration and uniformity of dosage.
• Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier or excipient .
• the compositions can be administered by any route compatible with a desired outcome.
• routes of administration include oral (e.g., ingestion or inhalation), intraperitoneal, intradermal, subcutaneous, intravenous, intraarterial, intracavity, intracranial, and parenteral.
• the compositions can also be administered using implants and microencapsulated delivery systems.
• compositions including pharmaceutical formulations can further include particles or a polymeric substance, such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, ethylene-vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers.
• a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, ethylene-vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers.
• Cyclopropanecarboxylic acid, cyclopropanecarboxylic acid and derivatives and modified forms thereof can be entrapped in microcapsules, for example, by the use of hydroxymethylcellulose or gelatin-microcapsules, or poly (methylmethacrolate) microcapsules, respectively, or in a colloid drug delivery system.
• a composition of the invention can of course be delivered to the target cell, organ or tissue by injection or infusion or the like.
• Targeting can be achieved by injection or infusion in practicing the methods of the invention.
• Targeting can also be achieved by using proteins that bind to a cell surface protein (e.g., receptor or matrix protein) present on the cell or population of cell types.
• antibodies or antibody fragments that bind to a cell surface protein can be included in the delivery systems in orderj to facilitate cell, tissue or organ targeting.
• Viral coat proteins that bind particular cell surface proteins can be used for targeting.
• naturally occurring or synthetic (e.g. recombinant) retroviral envelope proteins with known cell surface protein binding specificity can be employed in the- liposomes in order to intracytoplasmically deliver cyclopropanecarboxylic acid,- cyclopropanecarboxylic acid, and derivatives and modified forms thereof into target cells, tissue or organs.
• delivery vehicles including colloidal dispersion systems, can be made to have a protein coat in order to facilitate targeting or intracytoplasmic delivery of cyclopropanecarboxylic acid, cyclopropanecarboxylic acid and derivatives and modified forms thereof.
• the invention further provides a method for prophylactic and therapeutic treatments of various physiological condition or disorder treatable by increasing or improving glucose utilization in cells, tissue or organs of a patient by administering to the patient in need of such treatment, effective amounts of pharmaceutical compositions comprising substituted or unsubstituted cyclopropanecarboxylic acid, cyclopropanecarboxylic acid and cyclobutanecarboxylic acid derivative compounds represented by the Formulas (I), (Ilia) to (HIe) and (IIS).
• Disorders or conditions that can be treated with a method according to the present invention include, for example, ischemic/reperfusion injury, post myocardial infarction, angina, heart failure, a cardiomyopathy, peripheral vascular disease, diabetes,' and lacti-c acidosis, or symptoms or side effects associated with heart surgery (e.g., open heart surgery, bypass surgery, heart transplant) .
• the method according to the present invention includes administering a pharmaceutical compositions comprising effective amounts of substituted or unsubstituted cyclopropanecarboxylic acid, cyclopropanecarboxylic acid and cyclobutanecarboxylic acid derivative compounds represented by the Formulas (I),. (Ilia) to (HIe) and (IIS) in a single daily dose, or the total daily dosage may be administered in divided doses several times daily. Furthermore, the pharmaceutical compositions may be administered as a single dose or over a period of time.
• Patients that can be treated with the method according to the present invention include all known kind of mammals, including non human primates (apes, gibbons, chimpanzees, orangutans, macaques) , companion animals ⁇ dogs and cats) , farm animals (horses, cows, goats, sheep, pigs),, experimental animals (mouse, rat, rabbit, guinea pig) , and humans . . . . .
• the dosage regiment utilizing the pharmaceutical compositions according to the present invention is selected based on various factors such as type of physiological condition to be treated, age, weight, sex of the patient, severity of the conditions to be treated, the route of administration, and particular compound contained in the pharmaceutical composition ' .
• a physician or veterinarian of ordinary skill can readily determine and prescribed the effective amount of the pharmaceutical composition to prevent or to treat the specific physiological condition.
• the daily dosage may be varied over wide range and can be such that the amount of an active ⁇ comppund selected from a substituted cyclopropanecarbothioic acid or cyclobutanecarbothioic acid, or a substituted or an unsubstituted cyclopropanecarboxylic acid or cyclobutanecarboxylie acid derivative compound represented by any of Formulas (I), (IIS) and (Ilia) to (HIe). is sufficient to increase glucose utilization in a cell, tissue or organ of a warm blooded animal and to achieve the desired effect of alleviating or preventing fatty acid-induced ischemic damage.
• an active ⁇ comppund selected from a substituted cyclopropanecarbothioic acid or cyclobutanecarbothioic acid, or a substituted or an unsubstituted cyclopropanecarboxylic acid or cyclobutanecarboxylie acid derivative compound represented by any of Formulas (I), (IIS
• a kit typically includes a label or packaging insert including instructions for use, in vitro, in vivo, or ex vivo, of the components therein.
• packaging material refers to a physical structure housing the components of the kit, such as cyclopropanecarboxylic acid, cyclopropanecarboxylic acid or derivatives or modified forms thereof.
• the packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampules, etc.) «
• the label or packaging insert can include appropriate written instructions, for example, practicing a ' method of the invention.
• Kits of the invention therefore can additionally include instructions for using the kit components in a method of the invention.
• Instructions can include instructions for practicing any of the methods of the invention described herein.
• a kit can include a cyclopropanecarboxylic acid, cyclopropanecarboxylic acid or a derivative or modified form thereof in a pharmaceutical formulation in a container, pack, or dispenser together with instructions for administration to a human subj-ect.
• Instructions may additionally include indications of a satisfactory clinical endpoint or any adverse symptoms that may occur, or any additional information required by the Food and Drug Administration for use in humans.
• a kit may include instructions for increasing or improving glucose utilization in vitro, ex vivo or. in vivo.
• a kit includes instructions for treating a disorder associated with deficient or inefficient glucose utilization.
• the instructions comprise instructions for treating a subject- having or at risk of having ischemic/reperfusion injury, post myocardial infarction, angina, heart failure, a cardiomyopathy, peripheral vascular disease, diabetes, or lactic acidosis.
• the instructions comprise instructions for treating a subject having or at risk of having heart surgery (e.g., open heart surgery, bypass surgery, heart transplant and angioplasty) .
• kits may be on "printed matter," e.g.,- on paper or cardboard within the kit, or on a label affixed to. the kit or packaging material, or attached to a vial or tube containing a component of the kit.
• Instr ⁇ ctions may additionally be included on a computer readable medium, such as a disk (floppy diskette or hard disk) , optical CD such as CD- or DVD-ROM/RAM, magnetic tape, electronic storage media such as RAM and ROM and hybrids of these such as magnetic/optical storage media.
• Kits can additionally include a buffering agent, a preservative, or a stabilizing agent.
• kits can be enclosed within an individual container and- all of the various containers can be within a single package;
• the present invention is further illustrated in the following examples wherein all parts, percentages, and ratios are in equivalents, all temperatures are in 0 C, and all pressures are atmospheric unless otherwise indicated:
• Triethylene glycol monomethyl ether (1.1 eq, 5.2-6 mmol, 0.84 ml) and triethylamine (1.1 eq, 5.26 mmol, 0.73 ml) were taken in a 10 ml round bottom flask and dichloromethane (3 ml) was added. This mixture was cooled to 0°C and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5 g, 0.43 ml) was added in a dropwise fashion maintaining the temperature at 0 0 C with constant stirring.
• Triethylene glycol monomethyl ether (1.1 eq, 4.64 mmol, 0.74 ml) and triethylamine (1.1 eq, 4.64 mmol, 0.65 ml) were taken in a 25 ml round bottom flask and dichloromethane (3 ml) was added. This mixture was cooled to 0 0 C and then cyclobutanecarbonyl chloride (4.22 mmol, 0.5 g, 0.48 ml) was added in a dropwise fashion maintaining the temperature at 0 0 C with constant stirring (vigorous reaction) .
• the dichloromethane layer was separated from the aqueous layer, dried over anhydrous spdium sulphate, filtered, and evaporated in vacuo to give the title product as a pale yellowish-pink liquid.
• R 1 , R 2 , X, and n are defined in connection with Formula (I) and Z is H, alkyl (including cycloalkyl) , aryl or alkylcarbonyl.
• Suitable bases include triethylamine or pyridine.
• Suitable solvents include dichloromethane or other inert organic solvents.
• the compounds prepared, cycloalkyl carbonylchloride and alcohol starting materials used for their preparation and their molecular weights are summarized in Table 1.
• the compounds were characterized by 1 H NMR, 13 C NMR, IR . and mass spectroscopy.
• Example 2 The procedure of Example 2 was followed except that 2.5 equivalents of pyridine was used instead of 2 equivalents, cyclopropanecarbonyl chloride was used in place of cyclobutanecarbonylchloride and methyl ester alanine hydrochloride was used in place of methyl ester glycine hydrochloride.
• i Purified compound B (321 mg, 87%) was characterized by
• CD 3 OD ⁇ 176.28, 176.18, 49.38, 17.77, 14.59, 7.41, 7.33;
• Triethylene glycol (1.6 mmol, 0.24 g) and pyridine (2.2 eq, 3.52 mmol, 0.28 g, 0.28 ml) were taken in a 10 ml round bottom flask and dichloromethane (5 ml) was added. This mixture was cooled to O 0 C and then cyclopropanecarbonyl chloride (3.4 mmol, 0.36 g, 0.31 ml) was added in a dropwise fashion maintaining the temperature at 0 0 C with constant stirring. A white, thick suspension was observed after sometime. Stirring was continued for 1 hour at 0°C. The reaction was monitored by thin layer chromatography and then quenched with saturated ammonium chloride solution.
• Example 21 The procedure describe-d in Example 21 was followed using the following amounts of these reagents: triethyl-ene glycol (1.6 mmol, 0.24 g) , pyridine (2.2 eq, 3.52 mmol, 0.28 g, 0.28 ml); and cyclobutanecarbonyl chloride (3.4 mmol, 0.40 g, 0.39 ml) .
• 2-Isopropoxy-ethanol (1.1 eq, 3.04 mmol, 0.32 g, 0.35 ml), pyridine (0.5 eq, 1.38 mmol, 0.11 g, 0.11 ml), triethylamine (1.1 eq, 3.04 mmol, 0.31 g, 0.43 ml) were taken in a 10 ml round bottom flask and dichloromethane (6 ml) was added. This mixture was cooled to 0°C and then ( ⁇ ) - trans-2-phenyl-cyclopropanecarbonyl chloride (2.76 mmol, 0.5 g, 0.43 ml) was added in a dropwise fashion, maintaining the temperature at 0 0 C. A white precipitate was observed after sometime.
• This compound was prepared using the procedure described in Example 25 and using the following reagents: 2-ethoxy-ethanol (1.1 eq, 3.05 mmol, 0.27 g, 0.30 ml) pyridine (0.5 eq, 1.39 mmol, 0-.11 g, 0.11 ml), triethylamirie (1.1 eq, 3.05 mmol, 0.31 g, 0.43 ml); and ( ⁇ )-trans-2- phenyl- cyclopropanecarbonyl chloride (2.77 mmol, 0.5 g, 0.43 ml) .
• the compound was characterized by NMR ( 1 H and 13 C) , IR and mass spectroscopy:
• the compounds of Table 2B may be prepared using methods within the purview of one of skill in the art, including using methods similar and/or analogous to those described in Examples 1 to 27 and in the Detailed Description of the Invention and using the appropriate starting materials.
• Rat hearts were cannulated for isolated working heart 60 minute aerobic perfusions as described in J Pharmacol Exp Ther. 1993; 264:135-144, the -entire disclosure of which is incorporated herein by reference.
• mice Male Sprague-Dawley rats (0.3-0.35 kg) were anesthetized with pentobarbital sodium (60 mg/kg IP) and hearts were quickly excised, the aorta was cannulated and a retrograde perfusion at 37°C was initiated at a hydrostatic pressure of 60 mm Hg. Hearts were trimmed of excess tissue, and the pulmonary artery and the opening to the left atrium were then cannulated. After 15 min of Langendorff perfusion, hearts were switched to the working mode by clamping the aortic inflow line from the Langendorff reservoir and opening the left atrial inflow line. The perfusate was delivered from an oxygenator into the left atrium at a constant preload pressure of 11 mm Hg.
• Perfusate was ejected from spontaneously beating hearts into a compliance chamber (containing 1 ml of air) and into the aortic outflow line.
• the afterload was set at a hydrostatic pressure of 80 mm Hg.
• All working hearts were perfused with Kr-ebs'- Henseleit solution containing calcium 2.5 mmol/L, glucose 5.5 mmol/L, 3% bovine serum albumin (fatty acid free, initial fractionation by heat shock, Sigma), and with 1.2 mmol/L palmitate. Palmitate was bound to the albumin as described in J Bio Chem. 1992; 267:3825-3831, the entire disclosure of which is incorporated herein by reference.
• the perfusate was recirculated, and pH was adjusted to 7.4 by bubbling with a mixture containing 95% O 2 and 5% CO 2 .
• Heart rate and aortic pressure were measured with a Biopac Systems Inc. blood pressure transducer connected to the aortic outflow line.
• Cardiac output and aortic flow were measured with Transonic T206 ultrasonic flow probes in the preload and afterload lines, respectively.
• Coronary flow was calculated as the difference between cardiac output and aortic flow.
• Cardiac work was calculated as the product of systolic pressure and cardiac output.
• Glucose Oxidation was measured simultaneously by perfusing hearts with [U- 14 C] glucose according to the procedures discussed in Saddik M, et al., J Bio Chem. 1992; 267:3825-3831. The entire disclosure of this reference is incorporated herein by reference. The total myocardial 14 CO 2 production was determined at 10-min intervals from the 60-min aerobic period. Glucose oxidation rates were determined by quantitative measurement of 14 CO 2 production as described in Barbour RL, et al.,. Biochemistry. 1984; 1923: €503-60-62. The entire disclosure of this reference is incorporated herein by reference.
• Example A Glucose oxidation stimulation in untreated hearts and myocardial cells treated with various cyclopropanecarboxylic acid and cyclobutanecarboxylic acid derivatives .
• the procedure of Example A was followed except that various cyclobutanecarboxylic acid derivatives, cyclopropanecarboxylic acid derivatives and cyclobutanecarboxylic acid in the amounts of 1.00 ⁇ M or TOOO ⁇ M was added to the buffer in place of the cyclopropanecarboxylic acid, 2- [2- (2- methoxy-ethoxy) - ethoxy] -ethyl ester.
• TABLE 2A and TABLE 2B The results are illustrated in TABLE 2A and TABLE 2B.
• Example A The procedure of Example A was followed except that cyclobutanecarboxylic acid the amounts of -0.001 ⁇ M, 0.01 ⁇ M, 01 ⁇ M, 1 ⁇ M, 10 ⁇ M, and IOO ⁇ M was added to the buffer in place of the cyclopropanecarboxylic acid, 2- ⁇ 2-(2- methoxy-ethoxy) -ethoxy] -ethyl ester.
• cyclobutanecarboxylic acid the amounts of -0.001 ⁇ M, 0.01 ⁇ M, 01 ⁇ M, 1 ⁇ M, 10 ⁇ M, and IOO ⁇ M was added to the buffer in place of the cyclopropanecarboxylic acid, 2- ⁇ 2-(2- methoxy-ethoxy) -ethoxy] -ethyl ester.
• the results are illustrated in Figure 4.
• This assay is based on the method of Jackson, et al. Biochem J. 334:203-711 (1998). It is an adaptation of a pyruvate dehydrogenase (PDH) assay in which measures NADH (@ 340 nm) formed when pyruvate is converted to acetyl CoA. PDHK activity is measured as the amount of PDH activity remaining after ATP activation of PDHK, which in turn deactivates PDH.
• Pyruvate dehydrogenase enzyme complex (PDC) is purchased from Sigma. It contains intrinsic pyruvate dehydrogenase kinase (PDK) activity.
• PDC is pre-incubated in Buffer A (40 mM MOPS, pH 7.2, 0.5 mM EDTA, 30 mM KCl. 1.5 mM MgC12, -0.25 mM acetyl CoA, 0.05 mM NADH, 2 mM dithiothreitol, 10 mM NaF) for 40 minutes at 37° C. This step increases total PDH activity.
• Buffer A 40 mM MOPS, pH 7.2, 0.5 mM EDTA, 30 mM KCl. 1.5 mM MgC12, -0.25 mM acetyl CoA, 0.05 mM NADH, 2 mM dithiothreitol, 10 mM NaF
• the PDK reaction is started by adding 45.5 ⁇ l of pre-incubated enzyme (step 1) to 54.5 ⁇ l of PDK reaction solution (1.8x buffer A, 55 ⁇ M ADP + 100 ⁇ M ATP, ⁇ drug) .
• the reaction is run for 3 minutes @ 37° C and then stopped by adding 10 ⁇ l of Stop solution (55 mM ADP, 55 mM pyruvate) .
• PDH activity is then- assayed by adding 90 ⁇ l of Buffer B (120 mM Tris-HCl, pH 7.8, 0.61 mM EDTA, 0.73 mM MgC12, 2.2 mM cocarboxylase, 11 mM ⁇ -mercaptoethanol, 2.2 mM NAD, 2.2 mM pyruvate, 1.1 mM coenzyme A) and read at 340 nm kinetically for 2 minutes.
• Buffer B 120 mM Tris-HCl, pH 7.8, 0.61 mM EDTA, 0.73 mM MgC12, 2.2 mM cocarboxylase, 11 mM ⁇ -mercaptoethanol, 2.2 mM NAD, 2.2 mM pyruvate, 1.1 mM coenzyme A
• ( ) indicates volumes for kinase negative reactions used to determine total PDH activity.

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