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1.
Cell Immunol ; 197(2): 99-107, 1999 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-10607427

RESUMO

The voltage-gated potassium channel, Kv1.3, is specifically expressed on human lymphocytes, where it controls membrane potential and calcium influx. Blockade of Kv1.3 channels by margatoxin was previously shown to prevent T cell activation and attenuate immune responses in vivo. In the present study, a triterpene natural product, correolide, was found to block Kv1.3 channels in human and miniswine T cells by electrophysiological characterization. T cell activation events, such as anti-CD3-induced calcium elevation, IL-2 production, and proliferation were inhibited by correolide in a dose-dependent manner. More potent analogs were evaluated for pharmacokinetic profiles and subsequently tested in a delayed-type hypersensitivity (DTH) response to tuberculin in the miniswine. Two compounds were dosed orally, iv, or im, and both compounds suppressed DTH responses, demonstrating that small molecule blockers of Kv1.3 channels can act as immunosuppressive agents in vivo. These studies establish correolide and its derivatives as novel immunosuppressants.


Assuntos
Imunossupressores/farmacologia , Bloqueadores dos Canais de Potássio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio , Linfócitos T/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Humanos , Imunossupressores/química , Ativação do Canal Iônico , Canal de Potássio Kv1.3 , Estrutura Molecular , Suínos , Porco Miniatura , Linfócitos T/imunologia , Triterpenos/química
4.
J Med Chem ; 42(15): 2798-804, 1999 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-10425089

RESUMO

32-Indole ether derivatives of tacrolimus and ascomycin retain the potent immunosuppressive activity of their parent compounds but display reduced toxicity. In addition, their complexes with the 12-kDa FK506-binding protein (FKBP) form more stable complexes with the protein phosphatase calcineurin, the molecular target of these drugs. We have solved the three-dimensional structures of the FKBP complexes with two 32-indolyl derivatives of ascomycin. The structures of the protein and the macrolide are remarkably similar to those seen in the complexes with tacrolimus and ascomycin. The indole groups project away from the body of the complex, and multiple conformations are observed for the linkage to these groups as well as for a nearby peptide suggesting apparent flexibility in these parts of the structure. Comparison of these structures with that of the ternary complex of calcineurin, FKBP, and tacrolimus suggests that the indole groups interact with a binding site comprising elements of both the calcineurin alpha- and beta-chains and that this interaction is responsible for the increased stability of these complexes.


Assuntos
Imunofilinas/química , Imunossupressores/química , Indóis/química , Tacrolimo/análogos & derivados , Cristalografia por Raios X , Ligantes , Modelos Moleculares , Conformação Molecular , Conformação Proteica , Tacrolimo/química , Proteínas de Ligação a Tacrolimo
5.
Biochemistry ; 38(16): 4922-30, 1999 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-10213593

RESUMO

A novel nortriterpene, termed correolide, purified from the tree Spachea correae, inhibits Kv1.3, a Shaker-type delayed rectifier potassium channel present in human T lymphocytes. Correolide inhibits 86Rb+ efflux through Kv1.3 channels expressed in CHO cells (IC50 86 nM; Hill coefficient 1) and displays a defined structure-activity relationship. Potency in this assay increases with preincubation time and with time after channel opening. Correolide displays marked selectivity against numerous receptors and voltage- and ligand-gated ion channels. Although correolide is most potent as a Kv1.3 inhibitor, it blocks all other members of the Kv1 family with 4-14-fold lower potency. C20-29-[3H]dihydrocorreolide (diTC) was prepared and shown to bind in a specific, saturable, and reversible fashion (Kd = 11 nM) to a single class of sites in membranes prepared from CHO/Kv1.3 cells. The molecular pharmacology and stoichiometry of this binding reaction suggest that one diTC site is present per Kv1.3 channel tetramer. This site is allosterically coupled to peptide and potassium binding sites in the pore of the channel. DiTC binding to human brain synaptic membranes identifies channels composed of other Kv1 family members. Correolide depolarizes human T cells to the same extent as peptidyl inhibitors of Kv1.3, suggesting that it is a candidate for development as an immunosuppressant. Correolide is the first potent, small molecule inhibitor of Kv1 series channels to be identified from a natural product source and will be useful as a probe for studying potassium channel structure and the physiological role of such channels in target tissues of interest.


Assuntos
Ativação do Canal Iônico/efeitos dos fármacos , Bloqueadores dos Canais de Potássio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Linfócitos T/metabolismo , Triterpenos/química , Triterpenos/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Células CHO , Linhagem Celular , Charibdotoxina/farmacologia , Cricetinae , Humanos , Imunossupressores/antagonistas & inibidores , Imunossupressores/química , Imunossupressores/metabolismo , Imunossupressores/farmacologia , Canal de Potássio Kv1.3 , Potenciais da Membrana/efeitos dos fármacos , Neurotoxinas/farmacologia , Canais de Potássio/metabolismo , Radioisótopos de Rubídio/metabolismo , Venenos de Escorpião/farmacologia , Membranas Sinápticas/efeitos dos fármacos , Membranas Sinápticas/metabolismo , Linfócitos T/efeitos dos fármacos , Triterpenos/antagonistas & inibidores , Triterpenos/metabolismo
6.
Transplantation ; 65(1): 10-8, 1998 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-9448137

RESUMO

BACKGROUND: Tacrolimus (FK506) is an immunosuppressive drug 50-100 times more potent than cyclosporine (CsA), the current mainstay of organ transplant rejection therapy. Despite being chemically unrelated, CsA and tacrolimus exert their immunosuppressive effects through the inhibition of calcineurin (CaN), a critical signaling molecule during T-lymphocyte activation. Although numerous clinical studies have proven the therapeutic efficacy of drugs within this class, tacrolimus and CsA also have a strikingly similar profile of unwanted side effects. METHOD: Our objective has been to identify a less toxic immunosuppressant through the modification of ascomycin (FK520). Quantitative in vitro immunosuppression and toxicity assays have demonstrated (see the accompanying article, p. 18) that we achieved our goal with L-732,531 (indolyl-ascomycin; indolyl-ASC), a 32-O-(1-hydroxyethylindol-5-yl) ascomycin derivative with an improved therapeutic index relative to tacrolimus. RESULTS: We report that the attributes of indolyl-ASC may result from its distinctive biochemical properties. In contrast to tacrolimus, indolyl-ASC binds poorly to FK506 binding protein 12 (FKBP12), the major cytosolic receptor for tacrolimus and related compounds. However, the stability of the interaction between the FKBP12-indolyl-ASC complex and CaN is much greater than that of the FKBP12-tacrolimus complex. These distinguishing properties of indolyl-ASC result in the potent inhibition of CaN within T lymphocytes but may lower the accumulation of the drug at sites of toxicity. CONCLUSIONS: Indolyl-ASC may define those properties needed to increase the therapeutic efficacy of a macrolactam immunoregulant for treating both human autoimmune disease and organ transplant rejection.


Assuntos
Imunossupressores/farmacologia , Tacrolimo/análogos & derivados , Sequência de Bases , Inibidores de Calcineurina , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Divisão Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Interleucina-2/antagonistas & inibidores , Interleucina-2/genética , Células Jurkat , Linfócitos/efeitos dos fármacos , Substâncias Macromoleculares , Modelos Químicos , Dados de Sequência Molecular , Oligonucleotídeos Antissenso/metabolismo , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/metabolismo , Tacrolimo/farmacologia , Proteínas de Ligação a Tacrolimo
7.
Transplantation ; 65(1): 18-26, 1998 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-9448138

RESUMO

BACKGROUND: Tacrolimus (FK506) has potent immunosuppressive properties reflecting its ability to block the transcription of lymphokine genes in activated T cells through formation of a complex with FK506 binding protein-12, which inhibits the phosphatase activity of calcineurin. The clinical usefulness of tacrolimus is limited, however, by severe adverse effects, including neurotoxicity and nephrotoxicity. Although this toxicity, like immunosuppression, appears mechanistically related to the calcineurin inhibitory action of the drug, a large chemistry effort has been devoted to search for tacrolimus analogs with reduced toxicity but preserved immunosuppressive activity that might have enhanced therapeutic utility. METHODS: Here, we report on the identification of such an analog, which was synthetically derived from ascomycin (ASC), the C21 ethyl analog of tacrolimus, by introducing an indole group at the C32 position. The profile of biological activity of indolyl-ASC was characterized in rodent models of immunosuppression and toxicity. RESULTS: Indolyl-ASC was found to exhibit an immunosuppressive potency equivalent to that of tacrolimus in T-cell activation in vitro and in murine transplant models, even though indolyl-ASC bound about 10 times less to intracellular FK506 binding protein-12 than tacrolimus or ASC. Further evaluation of indolyl-ASC revealed that it is threefold less potent than tacrolimus in inducing hypothermia, a response that may reflect neurotoxicity, and in causing gastrointestinal transit alterations in mice. Moreover, indolyl-ASC was at least twofold less nephrotoxic than tacrolimus upon 3-week oral treatment in rats. CONCLUSIONS: Altogether, these data indicate a modest but definite improvement in the therapeutic index for indolyl-ASC compared with tacrolimus in rodent models.


Assuntos
Imunossupressores/farmacologia , Tacrolimo/análogos & derivados , Animais , Nitrogênio da Ureia Sanguínea , Temperatura Corporal/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Feminino , Imunossupressores/toxicidade , Ionomicina/farmacologia , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Tacrolimo/farmacologia , Tacrolimo/toxicidade , Glândula Tireoide/transplante
8.
Bioorg Med Chem Lett ; 8(16): 2253-8, 1998 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-9873523

RESUMO

A series of C32-O-aralkyl ether derivatives of the FK-506 related macrolide ascomycin have been prepared based on an earlier reported C32-O-cinnamyl ether design. In the present study, the nature of the aryl tethering group was varied in an attempt to improve oral activity. An imidazol-2-yl-methyl tether was found to be superior among those investigated and has resulted in an ascomycin analog, L-733,725, with in vivo immunosuppressive activity comparable to FK-506 but with an improved therapeutic index.


Assuntos
Imidazóis/síntese química , Imunossupressores/síntese química , Tacrolimo/análogos & derivados , Tacrolimo/síntese química , Animais , Disponibilidade Biológica , Hipotermia/induzido quimicamente , Imidazóis/farmacologia , Imidazóis/toxicidade , Imunofilinas/metabolismo , Imunossupressores/farmacologia , Imunossupressores/toxicidade , Indicadores e Reagentes , Rim/efeitos dos fármacos , Rim/patologia , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Estrutura Molecular , Neurotoxinas/toxicidade , Ratos , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Tacrolimo/toxicidade , Proteínas de Ligação a Tacrolimo
9.
J Med Chem ; 37(23): 4031-51, 1994 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-7966163

RESUMO

Systematic modification of the C6 acyl side chain of zaragozic acid A, a potent squalene synthase inhibitor, was undertaken to improve its biological activity. Simplification of the C6 side chain to the octanoyl ester has deleterious effects; increasing the linear chain length improves the in vitro activity up to the tetradecanoyl ester. An omega-phenoxy group is a better activity enhancer than an omega-phenyl group. A number of C6 carbamates, ethers, and carbonates were prepared and found to have similar activity profiles as the C6 esters. In the preparation of C6 ethers, C4 and C4,6 bisethers were also isolated; their relative activity is: C6 > C4 > C4,6. These C6 long-chain derivatives are subnanomolar squalene synthase inhibitors; they are, however, only weakly active in inhibiting hepatic cholesterol synthesis in mice. The C6 short-chain derivatives are much less active in vitro, but they all have improved oral activity in mice. Modification of the C1 alkyl side chain of the n-butanoyl analogue (ED50 4.5 mg/kg) did not improve the po activity further. A number of these C6 long-chain derivatives are also potent antifungal agents in vitro.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Compostos Bicíclicos com Pontes/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Ácidos Tricarboxílicos/farmacologia , Animais , Compostos Bicíclicos com Pontes/química , Candida albicans/enzimologia , Linhagem Celular Transformada , Feminino , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos DBA , Ratos , Relação Estrutura-Atividade , Ácidos Tricarboxílicos/química
10.
J Med Chem ; 37(3): 421-4, 1994 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-8308869

RESUMO

Chemistry that allows selective modification of the carboxylic acid groups of the squalene synthase inhibitor zaragozic acid A (1) was developed and applied to the synthesis of compounds modified at the 3-,4-,5-,3,4-,3,5-, and 4,5-positions. A key step in this procedure is the selective debenzylation by transfer hydrogenolysis in the presence of other olefinic groups. These compounds were tested in the rat squalene synthase assay and in vivo mouse model. Modification at C3 retains significant enzyme potency and enhances oral activity, indicating that C3 is not essential for squalene synthase activity. Modification at C4 and C5 results in significant loss in enzyme activity. In contrast, substitution at C3 or C4 enhances in vivo activity. Furthermore, disubstitution at the C3 and C4 positions results in additive in vivo potency.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Compostos Bicíclicos com Pontes/química , Ácidos Carboxílicos/química , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Ácidos Tricarboxílicos/química , Animais , Compostos Bicíclicos com Pontes/farmacologia , Esterificação , Masculino , Camundongos , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Ácidos Tricarboxílicos/farmacologia
12.
J Med Chem ; 35(19): 3474-82, 1992 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-1404229

RESUMO

(-)-trans-(2S,5S)-2-[3-[(2-Oxopropyl)sulfonyl]-4-n-propoxy-5-(3- hydroxypropoxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (10) is one of the most potent platelet-activating factor (PAF) antagonists in vitro and in vivo developed to date. This diaryltetrahydrofuran derivative evolved from modifications of MK 0287 which has been evaluated in clinical studies for asthma. Two structural modifications of MK 0287 were made: (1) elaboration of the 3'-[(hydroxyethyl)sulfonyl] group to a beta-keto propylsulfonyl, and (2) replacement of the 5'-methyl ether by a 3-hydroxypropyl ether. Compound 10 potently and specifically inhibits the binding of [3H]-C18-PAF to human platelet membranes (Ki 1.85 nM) and PMN membranes (Ki 2.89 nM). In vivo, 10 inhibits PAF-induced plasma extravasation and elevated N-acetyl-beta-D-glucosaminidase (NAGA) levels in male rats with ED50 values of 60 micrograms/kg, po and 4 micrograms/kg, iv respectively, and inhibits PAF-induced bronchoconstriction in guinea pigs with an ED50 value of 15 micrograms/kg after intraduodenal administration. Compound 15, a water-soluble phosphate ester prodrug derivative of 10 is at least equipotent to 10 in the in vivo models. Compound 19S, the primary and major metabolite of 10 and 15, is equipotent in in vitro and in vivo models.


Assuntos
Furanos/síntese química , Fator de Ativação de Plaquetas/antagonistas & inibidores , Pró-Fármacos/síntese química , Sulfonas/síntese química , Administração Oral , Animais , Furanos/química , Furanos/farmacologia , Cobaias , Humanos , Masculino , Inibidores da Agregação Plaquetária/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ratos , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia
13.
J Med Chem ; 34(9): 2692-701, 1991 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1895289

RESUMO

Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65 microM, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.


Assuntos
Renina/antagonistas & inibidores , Sequência de Aminoácidos , Simulação por Computador , Desenho de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Modelos Moleculares , Dados de Sequência Molecular , Relação Estrutura-Atividade
14.
Biochem Int ; 23(6): 1107-15, 1991 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1953807

RESUMO

Dehydrodipeptide analogs whose scissile carboxamide has been replaced with a PO(OH)CH2 group have been found to be potent inhibitors of the zinc protease dehydrodipeptidase 1 (DHP-1, renal dipeptidase, EC 3.4.13.11). The best of these inhibitors, compound 25 (Ki = 0.52 nM), is two hundred times more potent than cilastatin 2 which is used clinically as a component of the broad-spectrum antibiotic combination Primaxin. Compound 25 is a tight binding inhibitor exhibiting slow binding kinetics with a remarkably slow off rate from DHP-1 (half life greater than 8 hours). The kinetics of its binding are consistent with a simple on-off mechanism whereas the less active D-enantiomer 26 appears to bind in an initial loose complex with the enzyme which slowly rearranges to a tighter complex (Ki = 83 nM).


Assuntos
Dipeptidases/antagonistas & inibidores , Animais , Cilastatina/química , Cilastatina/farmacologia , Cinética , Estrutura Molecular , Especificidade por Substrato , Suínos
15.
J Med Chem ; 32(8): 1886-90, 1989 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-2502630

RESUMO

The dipeptide D-alanyl-D-alanine is an essential precursor of bacterial peptidoglycan; thus, blocking its formation is a possible target for the design of novel antibacterial agents. The synthesis of this dipeptide by bacterial D-alanine:D-alanine ligase requires ATP. In analogy with glutamine synthetase, we hypothesized a mechanism for this enzyme involving the intermediacy of D-alanyl phosphate. Several (3-amino-2-oxoalkyl)phosphonic acids and their analogues have been synthesized as possible inhibitory mimics of this proposed intermediate. The most active of them, (3(R)-amino-2-oxobutyl)phosphonic acid (8a) and the corresponding aza analogue (22), were effective ligase inhibitors although they had no significant antibacterial activity. The ligase inhibition of these compounds is consistent with an acyl phosphate displacement step in the mechanism of DAla-DAla ligase.


Assuntos
Antibacterianos/síntese química , Organofosfonatos/síntese química , Peptídeo Sintases/antagonistas & inibidores , Fenômenos Químicos , Química , Enterococcus faecalis/enzimologia , Organofosfonatos/farmacologia
16.
J Med Chem ; 32(8): 1681-5, 1989 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-2754692

RESUMO

A series of 1,3-substituted benzolactams are reported that are potent nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK). Design considerations were based upon the natural product CCK antagonist asperlicin and the potent benzodiazepine antagonist series exemplified by L-364,718 (1). Compound 19, the most potent compound in the benzolactam series, had an IC50 = 3 nM for inhibition of binding of 125I-CCK-8 to CCK receptors in rat pancreatic tissue, and its racemic analogue 8 was found to be orally active in inhibiting CCK-induced gastric emptying in mice, with an ED50 = 2.6 mg/kg po. The effects of ring size, substitution at positions 1 and 3, and stereochemistry at position 3 are discussed. Conformational studies of compound 19 and L-364,718 have delineated similarities that these molecules share in their core conformations and substituent orientations.


Assuntos
Colecistocinina/antagonistas & inibidores , Lactamas/síntese química , Animais , Benzodiazepinas/farmacologia , Fenômenos Químicos , Química , Lactamas/farmacologia , Camundongos , Conformação Molecular , Ratos
17.
J Med Chem ; 31(9): 1772-8, 1988 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-3137344

RESUMO

We report the synthesis of a series of phosphinic acid dipeptide analogues, NH2CH(R1)PO(OH)CH2CH(R2)CO2H, related to DAla-DAla. The best of these compounds are potent, essentially irreversible inhibitors of DAla-DAla ligase, and their preferred stereochemistry was shown by chiral synthesis of (1(S)-aminoethyl)(2(R)-carboxy-1-n-propyl)phosphinic acid, 12b, and by X-ray crystallography of its derivative benzyl [1(S)-[(benzyloxycarbonyl)-amino]ethyl](2(R)-carbomethoxy-1-propyl) phosphinate, 13, to correspond to the stereochemical configuration of DAla-DAla at both centers. A mechanism for the inhibition of DAla-DAla ligase by these compounds is proposed to involve an ATP-dependent formation of phosphorylated inhibitor within the enzyme's active site. The antibacterial activities of these compounds are modest although their spectra include both Gram-positive and Gram-negative susceptible organisms. The best antibacterial activity was shown by (1(S)-aminoethyl) [2-carboxy-2(R)-(methylthio)-1-ethyl]phosphinic acid, 3e, whose MIC's range from 4-128 micrograms/mL on nine of a panel of 11 bacterial organisms. Combination of one of the more active phosphinic acids 12b with the alanine racemase inhibitor fluoro-D-alanine enhances the antibacterial spectrum of the latter on several strains of bacteria and inhibits fluoro-D-alanine's self-reversal, which normally occurs at concentrations several fold higher than its MIC level. This inhibition of fluoro-D-alanine self-reversal is consistent with an involvement of DAla-DAla ligase inhibition in the antibacterial activity of these compounds.


Assuntos
Dipeptídeos/farmacologia , Peptídeo Sintases/antagonistas & inibidores , Ácidos Fosfínicos/farmacologia , Trifosfato de Adenosina/farmacologia , Sítios de Ligação , Fenômenos Químicos , Química , Ciclosserina/farmacologia , Dipeptídeos/síntese química , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/enzimologia , Testes de Sensibilidade Microbiana , Ácidos Fosfínicos/síntese química , Fosforilação , Proteus vulgaris/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos
18.
Biochem Biophys Res Commun ; 117(1): 108-13, 1983 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-6318742

RESUMO

A series of potent inhibitors of angiotensin-converting enzyme (dipeptidyl carboxypeptidase, E.C. 3.4.15.1) derived from benzofused 1-carboxyalkyl-3-(1-carboxy-3-phenyl-propylamino) lactams (III) is described. In the most effective inhibitors (I50 2-4 X 10(-9)M) the lactam is 7 or 8 membered and the N-1 side chain is carboxymethyl or carboxyethyl. Conformational and steric factors pertinent to binding to the enzyme are discussed.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Lactamas/síntese química , Indicadores e Reagentes , Lactamas/farmacologia , Conformação Molecular , Relação Estrutura-Atividade
19.
J Pharm Sci ; 69(1): 80-4, 1980 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-7354449

RESUMO

Binding parameters for a series of N-heterocyclic aminoethyl disulfides and thiosulfates to DNA were determined at different ionic strengths and pH values. None of the thiosulfates showed any binding ability, but the disulfides revealed DNA binding abilities that were suppressed both by increased ionic strength and hydrogen-ion concentration. No correlation between DNA binding ability and radiation protective activity in mice was evident.


Assuntos
DNA/metabolismo , Dissulfetos/metabolismo , Compostos Heterocíclicos/metabolismo , Protetores contra Radiação/metabolismo , Tiossulfatos/metabolismo , Sítios de Ligação , Dissulfetos/farmacologia , Humanos , Protetores contra Radiação/farmacologia , Tiossulfatos/farmacologia
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