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Biomedical subjects

A A Patchett

Publications and source records attributed to A A Patchett.

At least 73 records · Page 4Linked to original sources
PubMed1988

Phosphinic acid inhibitors of D-alanyl-D-alanine ligase.

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.

Adenosine Triphosphate↗
PubMed1988

Antibacterial activities of fluorovinyl- and chlorovinylglycine and several derived dipeptides.

The in vitro antibacterial activities of several halovinylglycine compounds and their L-norvalyl peptide derivatives are presented. The most potent of them, L-norvalyl-L-chlorovinylglycine, displayed good activity against gram-positive organisms, including methicillin-resistant Staphylococcus species. Chlorovinylglycine is an efficient inhibitor of alanine racemase, but the antibacterial activity of L-norvalyl-L-chlorovinylglycine may involve other physiological targets as well.

Anti-Bacterial Agents↗
PubMed1986

Conformationally restricted inhibitors of angiotensin converting enzyme: synthesis and computations.

A series of inhibitors of angiotensin converting enzyme (ACE, dipeptidyl carboxypeptidase, EC 3.4.15.1) is described which addresses certain conformational aspects of the enzyme-inhibitor interaction. In this study the alanylproline portion of the potent ACE inhibitor enalaprilat (2) is replaced by a series of monocyclic lactams containing the required recognition and binding elements. In order to more fully assess the lactam ring conformations and the key backbone angle psi as defined in 3 with respect to possible enzyme-bound conformations, a series of model lactams was investigated with use of molecular mechanics. The results point to a correlation between inhibitor potency (IC50) and the computed psi angle for the lowest energy conformation of the model compounds. Thus the psi angle as defined in 3 is an important determinant in the binding of inhibitors to ACE. The inhibition data in conjunction with the computational data have served to define a window of psi angles from 130 degrees to 170 degrees which seems to be acceptable to the ACE active site.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus.

A new, competitive, nonpeptide cholecystokinin (CCK) antagonist, asperlicin, was isolated from the fungus Aspergillus alliaceus. The compound has 300 to 400 times the affinity for pancreatic, ileal, and gallbladder CCK receptors than proglumide, a standard agent of this class. Moreover, asperlicin is highly selective for peripheral CCK receptors relative to brain CCK and gastrin receptors. Since asperlicin also exhibits long-lasting CCK antagonist activity in vivo, it should provide a valuable tool for investigating the physiological and pharmacological actions of CCK.

Animals↗
PubMed1985

Inhibition of rabbit lung angiotensin-converting enzyme by N alpha-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline and N alpha-[(S)-1-carboxy-3-phenylpropyl]L-lysyl-L-proline.

Two novel peptide analogs, N alpha-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline and the corresponding L-lysyl-L-proline derivative, have been demonstrated to be potent competitive inhibitors of purified rabbit lung angiotensin-converting enzyme: Ki = 2 and 1 X 10(-10) M, respectively, at pH 7.5, 25 degrees C, and 0.3 M chloride ion. Second-order rate constants for addition of these inhibitors to enzyme under the same conditions are in the range 1-2 X 10(6) M-1 s-1; first-order rate constants for dissociation of the EI complexes are in the range 1-4 X 10(-4) s-1. The association rate constants are similar to those measured for D-3-mercapto-2-methylpropanoyl-L-proline, captopril, but the dissociation rate constants are severalfold slower and account for the higher affinity of these inhibitors for the enzyme. The dissociation constant for the EI complex containing N alpha-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline is pH-dependent, and reaches a minimum at approximately pH 6: Ki = 4 +/- 1 X 10(-11) M. The pH dependence is consistent either with a model for which the protonation state of the secondary nitrogen atom in the inhibitor determines binding affinity, or one for which ionizations on the enzyme alone influence affinity for these inhibitors. The affinity of this inhibitor for the zinc-free apoenzyme is 2 X 10(4) times less than for the zinc-free apoenzyme is 2 X 10(4) times less than that for the holoenzyme. If considered as a "collected product" inhibitor, N alpha-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline appears to derive an additional factor of 375 M in its affinity for the enzyme compared to that of the two products of its hypothetical hydrolysis, a consequence of favorable entropy effects.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

The design and properties of N-carboxyalkyldipeptide inhibitors of angiotensin-converting enzyme.

Angiotensin-converting enzyme inhibitors promise to make important therapeutic contributions to the control of hypertension and congestive heart failure. The nonapeptide teprotide was the first of these inhibitors to be tested clinically. It was followed by orally active inhibitors, captopril in 1977 and enalapril in 1980. The latter is representative of a new design for the inhibition of metallopeptidases and is the subject of this review. The best of the N-carboxyalkyldipeptide inhibitors inhibits angiotensin-converting enzyme with a Ki of 7.6 X 10(-11) M. This compound is the most potent competitive inhibitor of a metallopeptidase yet to have been reported. The basis of this high potency is beginning to be understood and in part is considered to involve precisely arranged multiple interactions within the enzyme active site. X-ray crystallography of a thermolysin-inhibitor complex has been achieved. Assuming that similar interactions within the active site of angiotensin-converting enzyme are mechanistically probable, the authors hypothesize the binding of enalaprilat to converting enzyme as shown in Figure 24. Such interactions are consistent with kinetic studies (Section V) with the understanding that binding to the enzyme is not sensitive to the inhibitor's state of NH protonation. The reason for this surprising conclusion has not been established. Perhaps counterbalancing factors are involved in the energetics of binding or there may be compensating adjustments made in the enzyme which permit NH protonated and nonprotonated inhibitor to bind equally well. Figure 24 also summarizes present understanding of the conformation of enalaprilat when bound to angiotensin-converting enzyme. From studies on conformationally defined analogs of enalaprilat, it seems likely that the Ala-Pro segment of enalaprilat binds in a conformation that is close to a minimum energy conformer. This situation no doubt contributes to the potency of enalaprilat, since little binding energy would be needed to induce conformational changes in this part-structure of enalaprilat when it is bound to the enzyme. The phenethyl group of enalaprilat is believed to be near the alpha-hydrogen of the L-Ala residue in the enzyme-inhibitor complex. However, the synthesis of conformationally restricted analogs to establish this point has not yet been reached. The N-carboxyalkylpeptide design was developed from Wolfenden's collected product inhibitors of carboxypeptidase-A. Whether or not N-carboxyalkyldipeptides should be classified as collected product or transition state inhibitors is unclear.(ABSTRACT TRUNCATED AT 400 WORDS)

Aldosterone↗
PubMed1985

Angiotensin-converting enzyme inhibitors: synthesis and biological activity of acyl tripeptide analogues of enalapril.

The synthesis and biological activity of a series of inhibitors of angiotensin-converting enzyme (EC 3.4.15.1) are described. Incorporation of the substituted N-carboxymethyl dipeptide design of enalapril (MK-421) into acyl tripeptides and larger peptides yielded potent inhibitors of the enzyme. These can be viewed as substrate analogues in which the carbonyl of the scissile peptide bond is replaced by a CHCO2H group. Several of the analogues described possess inhibitory potency equal to that of enalaprilat (MK-422), but none achieves an increase in potency which would demonstrate additional binding interactions contributed by the extended peptide chain. Application of the design described may be useful for inhibition of other metallopeptidases.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Azapeptides: a new class of angiotensin-converting enzyme inhibitors.

A class of potent inhibitors of angiotensin-converting enzyme (dipeptidyl carboxypeptidase, E.C. 3.4.15.1) is reported, in which an alpha-aza substitution into the substituted N-carboxymethyl dipeptide structure of enalapril is made. The inhibitors 2 exhibit striking alterations in their conformational and acid-base properties due to the aza substitution, as is clear from pKa data and the x-ray crystal structure of a model azapeptide. In spite of this, they bind tightly to the enzyme, with inhibitor potency comparable to that of captopril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

The chemistry of enalapril.

The design origins of the potent non-mercapto angiotensin converting enzyme inhibitors enalaprilat and its mono ethyl ester enalapril are described. Lactam analogues of enalaprilat have provided some insight into the conformation of this inhibitor when it is bound to converting enzyme. X-ray crystallographic studies of a related enzyme/inhibitor complex offer an explanation for the high potency and specificity of these and related inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Carboxyl-terminal tripeptidyl hydrolysis of substance P by purified rabbit lung angiotensin-converting enzyme and the potentiation of substance P activity in vivo by captopril and MK-422.

The hydrolysis of substance P is catalyzed by purified rabbit lung angiotensin-converting enzyme (peptidyldipeptide hydrolase, EC 3.4.15.1). The kcat/Km for the reaction at 37 degrees is 3.3 +/- 0.3 X 10(3) M-1 sec-1, which is 60 times less than that which has been reported for the hydrolysis of angiotensin I. The initial site of hydrolysis is the antipenultimate peptide bond, which generates the tripeptide amide (Gly-Leu-Met-NH2). This hydrolysis is inhibited by the angiotensin-converting enzyme inhibitors captopril, MK-422, and EDTA, and is dependent on the concentration of chloride ion. Both captopril and MK-422 potentiate the substance P-induced stimulation of salivation in rats. Thus, angiotensin-converting enzyme may be one of the enzymes that degrade substance P in vivo.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

Benzolactams. A new class of converting enzyme inhibitors.

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.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

Inhibitors of glycolic acid oxidase. 4-substituted 2,4-dioxobutanoic acid derivatives.

Fourteen new 4-substituted 2,4-dioxobutanoic acids have been synthesized. These compounds, all of which contain lipophilic 4-substituents, are potent inhibitors in vitro of porcine liver glycolic acid oxidase. The I50 value of the two most potent representatives, 4-(4'-bromo[1,1'-biphenyl]-4-yl)-2, 4-dioxobutanoic acid (8) and 4-[4'-[[(3,4-dihydro-3-hydroxy-2H-1, 5-benzodioxepin-3-yl)methyl]thio][1,1'-biphenyl]-4-yl]-2, 4-dioxobutanoic acid (13) is 6 X 10(-8)M.

Alcohol Oxidoreductases↗
PubMed1982

Phosphorus-containing inhibitors of angiotensin-converting enzyme.

Several phosphonamides, phosphoramides, and phosphates having the general structure R-Y-P(O)(OH)-X-CH(CH3)-CO-Pro have been synthesized and tested for inhibition of angiotensin-converting enzyme (dipeptidyl carboxypeptidase; peptidyl-dipeptide hydrolase, EC 3.4.15.1). Inhibition was found to depend on the nature of R, Y, and X such that the maximal effect was observed when X = NH, Y = CH2, and R = phi CH2 (50% inhibition at 7 nM). Substitution of CH2 or O at X and O at Y produced significantly less potent inhibitors. Groups shorter or longer than R = phi CH2 led to less active inhibitors, presumably due to nonoptimal interaction of the side chain with the S1 subsite.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1981

Dihydromevinolin, a potent hypocholesterolemic metabolite produced by Aspergillus terreus.

A new, potent hypocholesterolemic agent is produced by cultures of Aspergillus terreus. The isolation of the compound and its characterization as 4a,5-dihydromevinolin containing a trans-fused octahydro-naphthalene system are described. Comparative data for dihydromevinolin and mevinolin in three biological assays are given: in vitro inhibition of HMG-CoA reductase, inhibition of sterol synthesis in cell cultures, and inhibition of cholesterol synthesis in vivo in rats.

Animals↗