Chemical similarities and differences among inhibitors of nitric oxide synthase, arginase and dimethylarginine dimethylaminohydrolase-1: Implications for the design of novel enzyme inhibitors modulating the nitric oxide pathway

Detection of nitric oxide-mediated metabolic effects using real-time extracellular flux analysis

“…Due to increasing availability and interest in inhibition of NOS enzyme activity, we next tested another commonly used iNOS inhibitor, 1400W, to see if it mirrored our previous results with SEITU. Since SEITU is a reversible pan-NOS enzyme inhibitor, it is an ideal iNOS inhibitor for studying short time points or for experiments where restoration of iNOS function is warranted ( Table 1 ) [ 35 ]. 1400W on the other hand is highly specific for the inducible NOS isoform (iNOS) and is irreversible, so that makes it optimal for studying processes where iNOS is the predominant NOS isoform, the enzyme needs to stay completely nonfunctional, or for experiments over extended periods of time ( Table 1 ) [ 35 ].…”

“…Since SEITU is a reversible pan-NOS enzyme inhibitor, it is an ideal iNOS inhibitor for studying short time points or for experiments where restoration of iNOS function is warranted ( Table 1 ) [ 35 ]. 1400W on the other hand is highly specific for the inducible NOS isoform (iNOS) and is irreversible, so that makes it optimal for studying processes where iNOS is the predominant NOS isoform, the enzyme needs to stay completely nonfunctional, or for experiments over extended periods of time ( Table 1 ) [ 35 ]. We hypothesized that regardless of the chemical and pharmacological differences between each of the drugs, that they would work similarly in terms of both inhibition of NO production and when used as injections during a mitochondrial stress test.…”

Recent advances in DDAH1 inhibitor design and discovery: insights from structure–activity relationships and X-ray crystal structures

“…Therefore, in certain disease states, indirect inhibition of NO synthesis may provide better therapeutic outcomes in regulating excess NO. 9 Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a key enzyme involved in the metabolism of asymmetric dimethylarginine (ADMA) to L-citrulline and dimethylamine. 9 ADMA and other substrates of DDAH1 (e.g., L-NMMA or monomethyl-L-arginine) function as potent endogenous NOS inhibitors (Fig.…”

“…9 Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a key enzyme involved in the metabolism of asymmetric dimethylarginine (ADMA) to l -citrulline and dimethylamine. 9 ADMA and other substrates of DDAH1 ( e.g. , L-NMMA or monomethyl- l -arginine) function as potent endogenous NOS inhibitors (Fig.…”

“…For instance, (i) the current DDAH1 inhibitors have low potency in the micromolar (μM) range; (ii) only a few inhibitors are selective for DDAH1; (iii) almost all DDAH1 inhibitors are based on the arginine scaffold; (iv) the pharmacokinetic characteristics of existing inhibitors have not been thoroughly tested and (v) not a single DDAH1 inhibitor has progressed to human trials. 9 The main reason for this is that compounds other than arginine/ornithine have not been researched thoroughly for DDAH1 inhibition. It is evident from a comparison of pharmacophore features and the chemical backbone of existing potent h DDAH1 inhibitors 13 , 20 , 26 , and 60 (Fig.…”