Oxoglutarate analogs

Subsequently, in a patent application, isoquinoline glycinamides such as 2 were claimed as collagen PHD inhibitors [40], and an additional patent application claimed isoquinoline glycinamides as HIF PHD inhibitors [41]. 

19 displayed IC50 values of 0.046, 0.351, and 0.111 iM for PHD2, CPH1, and CPH2, respectively, ketone analog 20 displayed IC50 values of 0.065, 40, and 13.4 iM, respectively. When 20 (50 mg/kg) was administered orally to rats, approximately a 25-fold increase in plasma EPO levels were observed relative to vehicle control [50]. 

Pyrimidine- and pyridazine-based analogs have recently emerged as PHD inhibitors and IC50 values in the range of 2-175 nM have been reported in a FRET-based PHD2 assay [52], A number of different substitutions ranging from alkyl, aryl, heteroaryl, and amino groups are accommodated in this series of compounds. While 1-pyrrolidinyl-, 23 and 1-piperidinyl-, 24, 

Other heterocyclic analogs including those containing the tetrahy-drofuro [57], tetrahydropyrrolo [58], and tetrahydrothieno [59] moieties have also been disclosed. These analogs displayed PHD2 IC50 values in the range of 10-100 nM. 

A group of benzimidazole-2-pyrazole PHD2 inhibitors appeared in a recent patent application, with IC50 values as low as 16 nM for compound 43 in a [14C]-based enzymatic assay [64]. Furthermore, members of this class of compounds were reported to stimulate erythropoietin secretion from PIep3B cells by up to 150% at 100 pM concentrations. 

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The scope of the condensation reaction has been extended considerably by varying the dicarbonyl compound employed. Diethyl 3-oxoglutarate, acetylacetone (2,4-pentanedione), and other compounds with structures analogous to that of ethyl acetoacetate, form compounds of constitution similar to that of II. 

On heating the parent acid of ester VI (from condensation of D-glucose with diethyl 3-oxoglutarate) in aqueous solution,11 following the procedure employed to obtain the corresponding derivative of ethyl acetoacetate XXVI, a sirup results. However, its change in optical activity shows a parallelism with that in analogous cases where crystalline products are isolated, and apparently indicates anhydride formation (see the last line in Table V). 

Transamination. Transamination with pyridoxal or analogs requires a metal catalyst such as Cu(II). However, transamination can be effected with DPL in combination with hexadecyltrimethylammonium chloride. By using these two reagents phenylglycine undergoes transamination with 2-oxoglutaric acid (equation I). 

The proposed catalytic mechanism of the ferredoxin oxidoreductase [32] is shown in Fig. 4, a similar mechanism existing for the analogous citric acid cycle enzyme, 2-oxoglutarate oxidoreductase. In outline, the 2-oxoacid is decarboxylated in a TPP-dependent reaction to give an hydroxyalkyl-TPP. From this, one electron is abstracted and transferred to the enzyme-bound iron-sulphur cluster, generating a free-radical-TPP species. This intermediate can then interact direct with coenzyme-A to form acyl-CoA, the iron-cluster receiving the second electron. In each case, ferredoxin serves to re-oxidise the enzyme s redox centre. 

The related substrate, 4-methyl-6-oxo-l-phenyl-l,6-dihydro-3,5-pyridazine-dicarbonitrile (154, R = Ph), and a-benzylidenemalononitrile (153) gave 8-amino-3-oxo-2,6-diphenyl-2,3-dihydro-4,7-cinnolinedicarbonitrile (155, R = Ph) [HN(CH2)s, pyridine, reflux, 4h 75%] analogs likewise. Ethyl 5-cyano-1 -o-methoxyphenyl-4-methyl-6-oxo-1,6-dihydro-3-pyridazinecar-boxylate (157) and diethyl 3-oxoglutarate (156) gave ethyl 4-cyano-6-ethoxycarbonylmethyl-8-hydroxy-2-o-methoxyphenyl-2,3-dihydro-7-cinnoU-necarboxylate (158) (AcOH, dioxane, reflux, 8h 79%) one analog... 

This decarboxylation reaction unlike reaction 3 is very similar to the oxidative decarboxylation of pyruvate. It is catalysed by 2-oxoglutarate dehydrogenase which is a multienzyme complex and requires the same cofactors as does the pyruvate dehydrogenase complex (page 232). The products of the reaction are succinyl-CoA, which is analogous to acetyl-CoA, and NADH. 

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