Pub Date : 2001-01-01DOI: 10.1080/14756360109162368
S. Mekapati, R. Sivakumar, S. Gupta
A Fujita-Ban type analysis has been made on a few series of HIV-1 (human immunodeficiency virus of type 1) protease inhibitors and the activity contributions of various substituents obtained. From these activity contributions, a compound is predicted that may have better activity than ritonavir, presently prescribed for the treatment of patients suffering from HIV-1. A few other compounds are also suggested.
{"title":"Quantitative Structure-Activity Relationship of some HIV-1 Protease Inhibitors: A Fujita-Ban Type Analysis","authors":"S. Mekapati, R. Sivakumar, S. Gupta","doi":"10.1080/14756360109162368","DOIUrl":"https://doi.org/10.1080/14756360109162368","url":null,"abstract":"A Fujita-Ban type analysis has been made on a few series of HIV-1 (human immunodeficiency virus of type 1) protease inhibitors and the activity contributions of various substituents obtained. From these activity contributions, a compound is predicted that may have better activity than ritonavir, presently prescribed for the treatment of patients suffering from HIV-1. A few other compounds are also suggested.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"17 1","pages":"185 - 197"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73321961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162394
Y. Imamura, T. Higuchi, M. Otagiri
Suprofen (SF) was little reduced by rabbit kidney carbonyl reductase, whereas its methyl ester (SPM) was an efficient substrate of the enzyme. To account for the differential catalytic activities for SF and SPM, the protective effects of these compounds against the inactivation of the enzyme by phenylglyoxal (PGO) were compared. Since the carboxyl group of SP is negatively charged and one essential arginine residue is known to be located in the NADPH-binding site of the enzyme, the protection of SP against the inactivation of the enzyme by PGO is expected to be more effective than that of SPM lacking a carboxyl group. However, the protective effects of SP and SPM were very similar. These results suggest that in spite of evidence for the binding of SP to the coenzyme-binding site, the carboxyl group of SP fails to interact with one essential arginine residue located in the site.
{"title":"Protective Effects of Suprofen and its Methyl Ester Against Inactivation of Rabbit Kidney Carbonyl Reductase by Phenylglyoxal","authors":"Y. Imamura, T. Higuchi, M. Otagiri","doi":"10.1080/14756360109162394","DOIUrl":"https://doi.org/10.1080/14756360109162394","url":null,"abstract":"Suprofen (SF) was little reduced by rabbit kidney carbonyl reductase, whereas its methyl ester (SPM) was an efficient substrate of the enzyme. To account for the differential catalytic activities for SF and SPM, the protective effects of these compounds against the inactivation of the enzyme by phenylglyoxal (PGO) were compared. Since the carboxyl group of SP is negatively charged and one essential arginine residue is known to be located in the NADPH-binding site of the enzyme, the protection of SP against the inactivation of the enzyme by PGO is expected to be more effective than that of SPM lacking a carboxyl group. However, the protective effects of SP and SPM were very similar. These results suggest that in spite of evidence for the binding of SP to the coenzyme-binding site, the carboxyl group of SP fails to interact with one essential arginine residue located in the site.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"224 1","pages":"451 - 455"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72674127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162391
A. Scozzafava, A. Mastrolorenzo, C. Supuran
Substituted urea derivatives were prepared by reacting 3,4-dichlorophenyl isocyanate with amino acids, dipeptides, histamine or dicyandiamide among others, or from N,N-diphenyl-carbamoyl chloride and amino acids, dipeptides, or histamine. Other derivatives were obtained by reaction of PABA or PAS with arylsulfonyl halides. Some of the new compounds showed appreciable activity as antimycobacterial agents against Mycobacterium tuberculosis H37Rv, producing an inhibition of growth in the range of 80–89%, at a concentration of 6.25 μM. Some derivatives of this series might constitute interesting lead molecules for designing novel types of drugs effective against M. tuberculosis, a re-emerging pathogen both in the developed and under-developed countries.
{"title":"Antimycobacterial Activity of 3,4-dichlorophenyl-ureas, N,N-diphenyl-ureas and Related Derivatives","authors":"A. Scozzafava, A. Mastrolorenzo, C. Supuran","doi":"10.1080/14756360109162391","DOIUrl":"https://doi.org/10.1080/14756360109162391","url":null,"abstract":"Substituted urea derivatives were prepared by reacting 3,4-dichlorophenyl isocyanate with amino acids, dipeptides, histamine or dicyandiamide among others, or from N,N-diphenyl-carbamoyl chloride and amino acids, dipeptides, or histamine. Other derivatives were obtained by reaction of PABA or PAS with arylsulfonyl halides. Some of the new compounds showed appreciable activity as antimycobacterial agents against Mycobacterium tuberculosis H37Rv, producing an inhibition of growth in the range of 80–89%, at a concentration of 6.25 μM. Some derivatives of this series might constitute interesting lead molecules for designing novel types of drugs effective against M. tuberculosis, a re-emerging pathogen both in the developed and under-developed countries.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"11 1","pages":"425 - 432"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80136115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162374
M. Balbaa, G. Yacout, Taysseer Ghonaim, Doaa Othman
Mammalian and hepatic aspartate transcarbamylase is inhibited by phenobarbital p-nitrophenylhydra-zone in a reversible and non-competitive type with Ki values 8.45 × 10−5 and 9.64×10−5 M in the reactions toward carbamyl phosphate and aspartate, respectively. In vivo inhibition occurred in a dose-dependent manner in which less than 50% of the activity was retained. These observations suggest that this inhibitor may interfere with the in vivo regulation of this enzyme and lead to an additional biological effect of phenobarbitals.
{"title":"Inhibition of Aspartate Transcarbamylase by a Phenobarbital Derivative","authors":"M. Balbaa, G. Yacout, Taysseer Ghonaim, Doaa Othman","doi":"10.1080/14756360109162374","DOIUrl":"https://doi.org/10.1080/14756360109162374","url":null,"abstract":"Mammalian and hepatic aspartate transcarbamylase is inhibited by phenobarbital p-nitrophenylhydra-zone in a reversible and non-competitive type with Ki values 8.45 × 10−5 and 9.64×10−5 M in the reactions toward carbamyl phosphate and aspartate, respectively. In vivo inhibition occurred in a dose-dependent manner in which less than 50% of the activity was retained. These observations suggest that this inhibitor may interfere with the in vivo regulation of this enzyme and lead to an additional biological effect of phenobarbitals.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"16 1","pages":"259 - 267"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88180165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162367
A. Alhomida
The effect of theophylline treatments on the activity of carnitine palmitoyltransferase (CPT) in skeletal muscle and the liver of rats was investigated. Theophylline was administered at 100 mg/kg bw/day and effects were monitored after a treatment period that lasted between a week and five weeks. Results showed that a significant increase in the activity of CPT was observed in skeletal muscle of theophyl-line-treated groups as compared to either control or placebo groups. However, there was no significant change in the activity of CPT in the hepatic tissues of theophylline-treated groups. The observed discrepancies in activity of CPT might be due to the presence of two isoenzymes, the muscle type (M-CPT) and liver type (L-CPT); it is possible that theophylline affects only M-CPT activity.
{"title":"Evaluation of Theophylline-Stimulated Changes in Carnitine Palmitoyltransferase Activity in Skeletal Muscle and Liver of Rats","authors":"A. Alhomida","doi":"10.1080/14756360109162367","DOIUrl":"https://doi.org/10.1080/14756360109162367","url":null,"abstract":"The effect of theophylline treatments on the activity of carnitine palmitoyltransferase (CPT) in skeletal muscle and the liver of rats was investigated. Theophylline was administered at 100 mg/kg bw/day and effects were monitored after a treatment period that lasted between a week and five weeks. Results showed that a significant increase in the activity of CPT was observed in skeletal muscle of theophyl-line-treated groups as compared to either control or placebo groups. However, there was no significant change in the activity of CPT in the hepatic tissues of theophylline-treated groups. The observed discrepancies in activity of CPT might be due to the presence of two isoenzymes, the muscle type (M-CPT) and liver type (L-CPT); it is possible that theophylline affects only M-CPT activity.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"11 1","pages":"177 - 183"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81329605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162393
C. D. Tormanen
Two isozyme forms of arginase are found in the rat. All arginases are metalloenzymes which require manganese for activity. Many arginases are activated by cobalt and nickel ions and inhibited by heavy metal ions. The purpose of this study was to compare the effect of other heavy metal ions on the rat liver isozyme (arginase I) and the rat kidney isozyme (arginase II). The activation and inhibition of arginase I and II by metal ions were different. However, both isozymes were strongly inhibited by cupric and mercuric ions. The inhibition of arginase I by cupric and mercuric ions was increased greatly by preincubation of the enzyme with the metal ions. However, preincubation of arginase II by cupric and mercuric ions had little effect on the inhibition of the enzyme. Under certain conditions the kinetics of the inhibition of both arginases I and II by cupric and mercuric ions was nonlinear allosteric.
{"title":"Allosteric Inhibition of Rat Liver and Kidney Arginase by Copper and Mercury Ions","authors":"C. D. Tormanen","doi":"10.1080/14756360109162393","DOIUrl":"https://doi.org/10.1080/14756360109162393","url":null,"abstract":"Two isozyme forms of arginase are found in the rat. All arginases are metalloenzymes which require manganese for activity. Many arginases are activated by cobalt and nickel ions and inhibited by heavy metal ions. The purpose of this study was to compare the effect of other heavy metal ions on the rat liver isozyme (arginase I) and the rat kidney isozyme (arginase II). The activation and inhibition of arginase I and II by metal ions were different. However, both isozymes were strongly inhibited by cupric and mercuric ions. The inhibition of arginase I by cupric and mercuric ions was increased greatly by preincubation of the enzyme with the metal ions. However, preincubation of arginase II by cupric and mercuric ions had little effect on the inhibition of the enzyme. Under certain conditions the kinetics of the inhibition of both arginases I and II by cupric and mercuric ions was nonlinear allosteric.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"1 1","pages":"443 - 449"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89357182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162390
T. K. Vinh, P. Nicholls, A. Kirby, C. Simons
A series of 4-aryl substituted 7-hydroxy-flavones were prepared using the three-step Baker-Venka-taraman synthesis in good overall yields. The flavones were all evaluated in vitro for inhibitory activity against aromatase (P450AROM/ CYP19), using human placental microsomes, and for inhibitory activity against 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD-1) using human placental cytosol. The phenyl, 4-fluoro-phenyl and 4-bromo-phenyl derivatives displayed moderate inhibitory activity against P450AROM (IC50 17.2, 13.5 and 10.1 μM, respectively), none of the flavones, including the standard genistein, displayed any inhibitory activity against 17β-HSD type 1 at 100 μM concentration.
{"title":"Evaluation of 7-Hydroxy-Flavones as Inhibitors of Oestrone and Oestradiol Biosynthesis","authors":"T. K. Vinh, P. Nicholls, A. Kirby, C. Simons","doi":"10.1080/14756360109162390","DOIUrl":"https://doi.org/10.1080/14756360109162390","url":null,"abstract":"A series of 4-aryl substituted 7-hydroxy-flavones were prepared using the three-step Baker-Venka-taraman synthesis in good overall yields. The flavones were all evaluated in vitro for inhibitory activity against aromatase (P450AROM/ CYP19), using human placental microsomes, and for inhibitory activity against 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD-1) using human placental cytosol. The phenyl, 4-fluoro-phenyl and 4-bromo-phenyl derivatives displayed moderate inhibitory activity against P450AROM (IC50 17.2, 13.5 and 10.1 μM, respectively), none of the flavones, including the standard genistein, displayed any inhibitory activity against 17β-HSD type 1 at 100 μM concentration.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"4 1","pages":"417 - 424"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88873770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162351
B. W. Clare, A. Scozzafava, C. Supuran
A series of compounds has been prepared by reaction of dicyandiamide with alkyl/arylsulfonyl halides as well as arylsulfonylisocyanates to locate a lead for obtaining weakly basic thrombin inhibitors with sulfonyldicyandiamide moieties as the SI anchoring group. The detected lead was sulfanilyl-dicyandiamide (Id of 3μM against thrombin, and 15μM against trypsin), which has been further derivatized at the 4-amino group by incorporating arylsulfonylureido as well as amino acyl/dipeptidyl groups protected at the amino terminal moiety with benzyloxycarbonyl or tosylureido moieties. The best compound obtained (ts-D-Phe-Pro-sulfanilyl-dicyan-diamide) showed inhibition constants of 9nM against thrombin and 1400 nM against trypsin. pKa measurements showed that the new derivatives reported here do indeed possess a reduced basicity, with the pKa of the modified guanidine moieties in the range 7.9–8.3 pKa units. Molecular mechanics calculations showed that the preferred tautomeric form of these compounds is of the type ArSO2N = C(NH2) NH-CN, probably allowing for the formation of favorable interaction between this new anchoring group and the active site amino acid residue Asp 189, critical for substrate/inhibitor binding to this type of serine protease. Thus, the main finding of the present paper is that the sulfonyldicyandiamide group may constitute an interesting alternative for obtaining weakly basic, potent thrombin inhibitors, which bind with less affinity to trypsin.
{"title":"Protease Inhibitors, Part 13: Specific, Weakly Basic Thrombin Inhibitors Incorporating Sulfonyl Dicyandiamide Moieties in their Structure","authors":"B. W. Clare, A. Scozzafava, C. Supuran","doi":"10.1080/14756360109162351","DOIUrl":"https://doi.org/10.1080/14756360109162351","url":null,"abstract":"A series of compounds has been prepared by reaction of dicyandiamide with alkyl/arylsulfonyl halides as well as arylsulfonylisocyanates to locate a lead for obtaining weakly basic thrombin inhibitors with sulfonyldicyandiamide moieties as the SI anchoring group. The detected lead was sulfanilyl-dicyandiamide (Id of 3μM against thrombin, and 15μM against trypsin), which has been further derivatized at the 4-amino group by incorporating arylsulfonylureido as well as amino acyl/dipeptidyl groups protected at the amino terminal moiety with benzyloxycarbonyl or tosylureido moieties. The best compound obtained (ts-D-Phe-Pro-sulfanilyl-dicyan-diamide) showed inhibition constants of 9nM against thrombin and 1400 nM against trypsin. pKa measurements showed that the new derivatives reported here do indeed possess a reduced basicity, with the pKa of the modified guanidine moieties in the range 7.9–8.3 pKa units. Molecular mechanics calculations showed that the preferred tautomeric form of these compounds is of the type ArSO2N = C(NH2) NH-CN, probably allowing for the formation of favorable interaction between this new anchoring group and the active site amino acid residue Asp 189, critical for substrate/inhibitor binding to this type of serine protease. Thus, the main finding of the present paper is that the sulfonyldicyandiamide group may constitute an interesting alternative for obtaining weakly basic, potent thrombin inhibitors, which bind with less affinity to trypsin.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"42 1","pages":"1 - 13"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84622588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N-(n-butyl)thiophosphorictriamide (NBPT) and its oxygen analogue N-(n-butyl)phosphorictriamide (NBPTO) were studied as inhibitors of jack bean urease. NBPTO was obtained by spontaneous conversion of NBPT into NBPTO. The conversion under laboratory conditions was slow and did not affect NBPT studies. The mechanisms of NBPT and NBPTO inhibition were determined by analysis of the reaction progress curves in the presence of different inhibitor concentrations. The obtained plots were time-dependent and characteristic of slow-binding inhibition. The effects of different concentration of NBPT and NBPTO on the initial and steady-state velocities as well as the apparent first-order velocity constants obeyed the relationships for a one-step enzyme-inhibitor interaction, qualified as mechanism A. The inhibition constants of urease by NBPT and NBPTO were found to be 0.15 μM and 2.1 nM, respectively. The inhibition constant for NBPT was also calculated by steady-state analysis and was found to be 0.13 μM. NBPTO was found to be a very strong inhibitor of urease in contrast to NBPT.
{"title":"Inhibition of Jack Bean Urease by N-(n-butyl)thiophosphorictriamide and N-(n-butyl)phosphorictriamide: Determination of the Inhibition Mechanism","authors":"M. Kot, W. Zaborska, Kinga Orlinska","doi":"10.1080/14756360127569","DOIUrl":"https://doi.org/10.1080/14756360127569","url":null,"abstract":"N-(n-butyl)thiophosphorictriamide (NBPT) and its oxygen analogue N-(n-butyl)phosphorictriamide (NBPTO) were studied as inhibitors of jack bean urease. NBPTO was obtained by spontaneous conversion of NBPT into NBPTO. The conversion under laboratory conditions was slow and did not affect NBPT studies. The mechanisms of NBPT and NBPTO inhibition were determined by analysis of the reaction progress curves in the presence of different inhibitor concentrations. The obtained plots were time-dependent and characteristic of slow-binding inhibition. The effects of different concentration of NBPT and NBPTO on the initial and steady-state velocities as well as the apparent first-order velocity constants obeyed the relationships for a one-step enzyme-inhibitor interaction, qualified as mechanism A. The inhibition constants of urease by NBPT and NBPTO were found to be 0.15 μM and 2.1 nM, respectively. The inhibition constant for NBPT was also calculated by steady-state analysis and was found to be 0.13 μM. NBPTO was found to be a very strong inhibitor of urease in contrast to NBPT.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"49 1","pages":"507 - 516"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90822985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162371
Hui-Yao Huang, P. Martásek, L. Roman, R. Silverman
Selective inhibition of the isoforms of nitric oxide synthase (NOS) could be beneficial in the treatment of certain disease states arising from the overproduction of nitric oxide by NOS. Recently, we reported dipeptide amides containing a basic amine side chain as potent and selective inhibitors of neuronal NOS (Huang, H. et al. (1999) J. Med. Chem., 42, 3147). The most potent nNOS inhibitor among these compounds is L-ArgNO2-L-Dbu-NH2 (1) (Ki = 130nM), which also exhibits the highest selectivity over eNOS (> 1500-fold). The D,D-dipeptide, D-Lys-D-ArgNO2-NH2 (3) also shows high potency and selectivity. Here the dipeptide amides containing ArgNO2 and D-Dbu (9–12) were synthesized and evaluated. They are all modest inhibitors of nNOS, but poor inhibitors of eNOS and iNOS. D-Dbu-D-ArgNO2-NH2 (12) exhibits decreased inhibitory potency as compared with 3. A hypothesis regarding the binding at the active site of nNOS is proposed to explain the potency differences between the L- and D-form dipeptide amides.
选择性抑制一氧化氮合成酶(NOS)的同工异构体可能有助于治疗由一氧化氮过量产生引起的某些疾病状态。最近，我们报道了含有碱性胺侧链的二肽酰胺是神经元NOS的有效和选择性抑制剂(Huang, H. et al. (1999) J. Med. Chem。， 42, 3147)。其中，L-ArgNO2-L-Dbu-NH2 (1) (Ki = 130nM)对eNOS的选择性最高(> 1500倍)。D,D-二肽，D- lys -D- argno2 - nh2(3)也显示出高的效价和选择性。本文合成并评价了含ArgNO2和D-Dbu(9-12)的二肽酰胺。它们都是nNOS的适度抑制剂，但对eNOS和iNOS的抑制作用较差。与3相比，D-Dbu-D-ArgNO2-NH2(12)表现出较低的抑制效力。提出了一个关于nNOS活性位点结合的假设，以解释L型和d型二肽酰胺之间的效价差异。
{"title":"Synthesis and Evaluation of Dipeptide Amides Containing Nω-Nitroarginine and D-2, 4-Diaminobutyric Acids as Inhibitors of Neuronal Nitric Oxide Synthase","authors":"Hui-Yao Huang, P. Martásek, L. Roman, R. Silverman","doi":"10.1080/14756360109162371","DOIUrl":"https://doi.org/10.1080/14756360109162371","url":null,"abstract":"Selective inhibition of the isoforms of nitric oxide synthase (NOS) could be beneficial in the treatment of certain disease states arising from the overproduction of nitric oxide by NOS. Recently, we reported dipeptide amides containing a basic amine side chain as potent and selective inhibitors of neuronal NOS (Huang, H. et al. (1999) J. Med. Chem., 42, 3147). The most potent nNOS inhibitor among these compounds is L-ArgNO2-L-Dbu-NH2 (1) (Ki = 130nM), which also exhibits the highest selectivity over eNOS (> 1500-fold). The D,D-dipeptide, D-Lys-D-ArgNO2-NH2 (3) also shows high potency and selectivity. Here the dipeptide amides containing ArgNO2 and D-Dbu (9–12) were synthesized and evaluated. They are all modest inhibitors of nNOS, but poor inhibitors of eNOS and iNOS. D-Dbu-D-ArgNO2-NH2 (12) exhibits decreased inhibitory potency as compared with 3. A hypothesis regarding the binding at the active site of nNOS is proposed to explain the potency differences between the L- and D-form dipeptide amides.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"40 1","pages":"233 - 239"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85753036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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