Pyrimidine kinase

Reddick, J.J. Kinsland, C. Nicewonger, R. Christian, T Downs, D.M. Winkler, M.E. Begley, T.P. Overexpression, purification and characterization of two pyrimidine kinases involved in the biosynthesis of thiamin 4-amino-5-hydroxymethyl-2-methylpyrimidine kinase and 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate kinase. Tetrahedron, 54, 15983-15991 (1998)... 

Phosphomethyl pyrimidine kinase S. aureus NCTC 8325 Primary metabolism... 

Figure 1.8 A range of 2,4-diamino pyrimidine kinase inhibitors.

H. Daub, Chemical proteomic analysis reveals alternative modes of action for Pyrido[2,3-d]pyrimidine kinase inhibitors, Mol. Cell. Proteomics 2004,... 

S Additional information <2, 4> (<4> enzyme is probably different from previously isolated HMP kinase, because the subunit molecular masses are significantly different [4] <4> bifunctional hydroxymethylpyrimidine kinase/phosphomethylpyrimidine kinase [5] <2> bifunctional hydroxy-pyrimidine kinase/thiamin-phosphate pyrophosphorylase [3]) [3-5]... 

What is the mechanism of this drug induced interference with pyrimidine metabolism The finding of orotic acid and orotidine in the urine is similar to that seen after therapy with the drug 6-azauridine. This compound is converted by a pyrimidine kinase to 6-azauridylic acid which competitively inhibits ODC (Handschumacher, 1960). By analogy a nucleotide derivative of allopurinol, oxipurinol or a metabolite may be a competitive inhibitor of ODC. In addition, a purine or pyrazolopyrimidine base could act as an inhibitor of OPRT or both mechanisms could work in concert. Finally, depletion of an essential substrate such as PP-ribose-P could also contribute. 

Biosynthesis of pyrophosphate (5) from pyrimidine phosphate (47) and thia2ole phosphate (48) depends on the activity of five en2ymes, four of them kinases (87). In yeasts and many other organisms, including humans, pyrophosphate (5) can be obtained from exogenous thiamine in a single step cataly2ed by thiamine pyrophosphokinase (88). 

Basically, AZT is anabohcaHy phosphorylated to AZT mono-, di-, and tri-phosphates by various enzymes (kinases) of a target ceU (159). AZT-triphosphate competes with other phosphorylated pyrimidine nucleosides for incorporation into HIV DNA by the viral reverse transcriptase. Incorporation of the AZT-triphosphate into reverse transcriptase results in viral DNA chain termination. Reverse transcriptase is essential in the repHcative cycle of HIV. 

While mammahan cells reutilize few free pyrimidines, salvage reactions convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2 "-de-oxycytidine, 2 -deoxyguanosine, and 2 -deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP). 

The RBC contains certain enzymes of nucleotide metabolism (eg, adenosine deaminase, pyrimidine nucleotidase, and adenylyl kinase) deficiencies of these enzymes are involved in some cases of hemolytic anemia. 

Experimental screening established that compound 42 shown in Fig. 8.11 disrupts ZipA-FtsZ protein-protein interaction. However, previous studies suggested potential issues with toxicity associated with this class of compounds. Additionally such amine-substituted pyridyl-pyrimidines are heavily patented in the context of kinase inhibition. Both of these factors limit the scope of the subsequent lead optimization process, to transform this compound into a viable drug. Knowledge that compound 42 was a micromolar inhibitor of ZipA-FtsZ was exploited by searching for molecules that were similar in shape. 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

Cross-reactivity with JAK kinases is a recurring theme with pyrimidine-carboxamides [81,82], but compound 20 exemplifies a Syk-selective series [81]. Pyrimidine amide 20 has an IC50 of 6nM against Syk, and broad screening (at 300 nM concentration) demonstrated significant selectivity for Syk over 270 kinases. In Ramos cells, 20 inhibited BCR-induced phosphorylation of BLNK, a direct substrate of Syk, with an EC50 of 500-750 nM and Ca2+ flux with an EC50 = 117 nM. Compound 20 potently... 

Within an SAR study of p38 MAP kinase inhibitors, a series of 3,4-dihydropyrimido[4,5-ri pyrimidin-2-ones and 3,4-dihydropyrido[4,3-rijpyrimidin-2-ones were prepared <06BMCL4400>. 

The synthesis of some novel acyclonucleosides involving pyrrolo[2,3-c]pyridazine and a 4-hydroxybutyl side chain has been reported <00H(53)5>. New pyrrolo[2,3-pyrimidines containing an extended 5-substituent, as potent and selective inhibitors of lck (an src-family tyrosine kinase), have been synthesized and tested <00BMCL2171>. 

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