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PubMed1992

Inhibition of human serine proteases by substituted 2-azetidinones.

trans-4-Ethoxycarbonyl-3-ethyl-1-(4-nitrophenyl-sulfonyl)-azetidin -3-one described by Firestone et al. (1990, Tetrahedron 46, 2255) as an inhibitor of human leucocyte elastase (HLE) displayed potent, time-dependent inhibition of both HLE and human cathepsin G (Cat-G). The cis-isomer was 7- and 180-fold less active, respectively. The mechanism likely involves opening of the beta-lactam ring by the active site serine to form an acyl-enzyme intermediate(s). This intermediate partitions with ratios of 4:1 between turnover of the inhibitor and formation of relatively stable enzyme-inhibitor complexes from both enzymes. The final HLE-inhibitor complex reactivated with a half-life of 48 h at 25 degrees C and was 16-fold more stable than the Cat-G-inhibitor complex. The stability of the acyl-enzymes supports a "double hit" chemical mechanism involving both serine acylation and alkylation of the histidine. These observations suggest that beta-lactams may be developed as a class of serine protease inhibitors.

Azetidines↗
PubMed1975

Effect of colchicine on collagen, albumin and transferrin synthesis by cirrhotic rat liver slices.

Collagen synthesis was found to be increased in liver slices of rats made cirrhotic by chronic administration of CCl4. The liver function was impaired, as determined by an increased retention of conjugated bilirubin and low serum albumin values. However, when animals received colchicine simultaneously with CCl4, collagen synthesis and deposition were inhibited, and the liver function appeared normal. When a group of rats was made cirrhotic by chronic administration of CCl4, and then kept for 30 days without further treatment, fibrosis persisted and collagen synthesis was very low. However, the liver function was severely impaired. When similar rats received L-azetidine-2-carboxylic acid during the 30-days period following CCl4 administration, there was a slight but not significant improvement in liver function. The collagen synthesis and the extent of fibrosis were similar to the controls. However, if similar rats received colchicine during the 30 days period, collagen synthesis was almost negligible, there was a slight decrease in fibrosis and there was a great improvement in liver function. In all the cirrhotic animals studied, transferrin biosynthesis remained constant.

Animals↗
PubMed2004

Synthesis of antitumor 6-alkylidenepenicillanate sulfones and related 3-alkylidene-2-azetidinones.

6-alkylidenepenicillanate sulfoxides and sulfones were synthesized on the base of 6-oxopenicillanate esters. The targeted splitting of their thiazolidine ring led to the formation of 3-alkylidene substituted 4-heteryldithio and 4-methylsulfonyl azetidin-2-ones. Some of mono and bicyclic beta-lactams revealed potent cytotoxic properties towards monolayer tumor cells in <10-microM concentrations.

Animals↗
PubMed2004

Synthesis and anti-HCMV activity of 1-acyl-beta-lactams and 1-acylazetidines derived from phenylalanine.

Different Phe-derived 1-acyl-beta-lactams, analogous to a series of 2-azetidinones acting as HCMV serine protease inhibitors, were synthesized. Some of these compounds were modest inhibitors of the HCMV replication. Interestingly, removal of the carbonyl group of the beta-lactam ring, most likely acting as the serine trap, resulted in an azetidine derivative with anti-HCMV activity comparable to that of the reference compound ganciclovir.

Antiviral Agents↗
PubMed2005

3,4-disubstituted azetidinones as selective inhibitors of the cysteine protease cathepsin K. Exploring P3 elements for potency and selectivity.

The synthesis of a series of highly potent and selective inhibitors of cathepsin K based on the 3,4-disubstituted azetidin-2-one warhead is reported. A high degree of potency and selectivity was achieved by introducing a basic nitrogen into the distal part of the P3 element of the molecule. Data from kinetic and mass spectrometry experiments are consistent with the interpretation that compounds of this series transiently acylate the sulfhydrile of cathepsin K.

Azetidines↗
PubMed2002

Reinvestigation of the iodocyclization of 4,5,7-tri-O-benzyl-3-(N-benzylacetamido)-1,2,3-trideoxy-D-gluco-hept-1-enitol: unexpected formation of a 1,3-imino-heptitol derivative.

The NIS-mediated iodocyclization of 4,5,7-tri-O-benzyl-3-(N-benzylacetamido)-1,2,3-trideoxy-D-gluco-hept-1-enitol gave unexpectedly a 1,3-imino-heptitol derivative, namely 2-O-acetyl-N-benzyl-4,5,7-tri-O-benzyl-1,3-dideoxy-1,3-imino-D-glycero-D-ido-heptitol. This compound is a new example of a rare class of azetidine imino alditol derivatives which have interesting properties such as glycosidase inhibitors. The physical and spectral data for this imino heptitol were essentially identical to those reported for 2,6-anhydro-4,5,7-tri-O-benzyl-3-(N-benzylacetamido)-3-deoxy-D-glycero-D-ido-heptitol, a derivative of C-(2-acetamido-2-deoxy-alpha-D-glucopyranosyl)methanol obtained from the same precursor [Lay, L.; Nicotra, F.; Panza, L.; Verani, A. Gazz. Chim. Ital. 1992, 122, 345-348]; these findings cast doubts on the structure reported for the latter product.

Acetamides↗
PubMed1986

Reversed-phase high-performance liquid chromatographic assay for the determination of potency and impurities in tazadolene succinate bulk drug and capsules.

A reversed-phase assay based on high-performance liquid chromatography with a water-acetonitrile-tetrahydrofuran (THF)-triethylamine (TEA)-perchloric acid (pH 2.5) mobile phase and a Zorbax C8 column has been validated for the determination of the purity of tazadolene succinate (I) [E-(+/-)-1-(2-benzylidenecyclohexyl)azetidine succinate, U-53996H] bulk drug, the potency of tazadolene succinate hard-filled capsule formulations and impurity levels in bulk drug. The system resolves E- and Z-isomers and other structurally related molecules. Retention of these compounds is mainly dependent on the amount of acetonitrile and THF in the mobile phase. An amine must be present in the mobile phase to bring about elution of I. The potency assay utilizes testosterone as internal standard. Potency assays exhibited relative standard deviations (R.S.D.) of less than 1%. Quantitative recovery from hard-filled capsules (HFC) is obtained by using a simple extraction procedure. Potential process impurities, potential degradation products, and formulation excipients are resolved. The assay is linear for tazadolene succinate concentrations equivalent to 50-150% of the assay concentration. Impurities can be quantitated to levels equivalent to about 0.1% by weight with R.S.D. less than 5%. The estimated limit of detection for I is about 2 ng for a 20 microliters injection.

Analgesics↗
PubMed2002

Beneficial effects of cardiac chymase inhibition during the acute phase of myocardial infarction.

Recently, the presence of the chymase-dependent angiotensin (Ang) II-generating system in hamsters, dogs, monkeys, as well as human cardiovascular tissues has been identified. We have reported that the activation of cardiac chymase was more prominent than that of angiotensin converting enzyme (ACE) and that AT1 receptor antagonist treatment rather than ACE inhibitor treatment alone provided significant beneficial effects on cardiac function and survival after MI in hamsters. The aim of the present study was to determine whether this different effects between AT1 receptor antagonist and ACE inhibitor were due to the activation of cardiac chymase after MI in hamsters by using 4-[1-[[bis-(4-methyl-pheny)-methyl]-carbamoyl]-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid (BCEAB), a novel, orally active and specific chymase inhibitor. The ACE and chymase activities in the infarcted left ventricle were significantly increased 3 days after MI. BCEAB (100 mg/kg/day, p.o.) treatment starting 3 days before MI significantly suppressed the cardiac chymase activity, while it did not affect the plasma and cardiac ACE activities 3 days after MI. A significant improvement in hemodynamics (maximal negative and positive rates of pressure development; left ventricular systolic pressure) was observed for the treatment with BCEAB 3 days after MI. BCEAB (100 mg/kg/day, p.o.) treatment starting 3 days before MI significantly reduced the mortality rate during 14 days of observation following MI (vehicle, 61.1%, n = 18; BCEAB, 27.8%, n = 18; P < 0.05). These findings demonstrated for the first time that cardiac chymase participates directly in the pathophysiologic state after MI in hamsters.

Acute Disease↗
PubMed1999

Characterization and expression of the mouse Hsc70 gene.

A genomic clone encoding the mouse Hsc70 gene has been isolated and characterized by DNA sequence analysis. The gene is approximately 3. 9 kb in length and contains eight introns, the fifth, sixth and eighth of which encode the three U14 snoRNAs. The gene has been located on Chr 9 in the order Fli1-Itm1-Olfr7-Hsc70(Rnu14)-Cbl by genetic analysis. Expression of Hsc70 is universal in all tissues of the mouse, but is slightly elevated in liver, skeletal muscle and kidney tissue, while being depressed in testes. In cultured mouse NIH 3T3 cells or human HeLa cells, Hsc70 mRNA levels are low under normal conditions, but can be induced 8-fold higher in both lines by treatment with the amino acid analog azetidine. A similar induction is seen in cells treated with the proteosome inhibitor MG132 suggesting that elevated Hsc70 expression may be coupled to protein degradation. Surprisingly, expression of the human Hsc70 gene is also regulated by cell-cycle position being 8-10-fold higher in late G1/S-phase cells as opposed to the levels in early G1-phase cells.

3T3 Cells↗
PubMed1996

Interaction of human leukocyte elastase with a N-aryl azetidinone suicide substrate: Conformational analyses based on the mechanism of action of serine proteinases.

The three-dimensional interaction of the enzyme-activated (suicide) inhibitor AA 231-1 [N-(2-chloromethyl)-3, 3-difluoro-azetidin-2-one] with human leukocyte elastase has been studied using computer graphics and molecular mechanics. Systematic conformational analyses and energy minimizations have been performed for the inhibitor AA 231-1 and its presumed complexes formed during the enzymatic process of inactivation, i.e., the Michaelis complex, the acyl-enzyme, and the inactivated enzyme with the covalently bound inhibitor. The beta-lactam ring characteristics of modeled AA 231-1 were in agreement with crystallographic data of related structures. Lowest energy conformations were found when the angle between the planes of the beta-lactam ring and that of its phenyl substituent was about -60 or 60 degrees. To study the interaction with the enzyme, the enzyme-inhibitor complexes were constructed by docking the inhibitor in the active site using enzyme coordinates from an X-ray crystallographic structure. The whole enzyme structure was used for conformational analyses and energy mechanics. Favorable conformations for the Michaelis complex have been obtained in which the carbonyl oxygen of the inhibitor was located in the oxyanion hole and the hydroxyl of Ser195 was in position to interact with the beta-lactam carbonyl carbon on the alpha face of AA 231-1. Simulations of the approach of the benzylic carbon by the nucleophilic amino acid His40 or His57 through an SN2 displacement on the halomethyl group of AA 231-1 were performed. The results agreed with the alkylation of the imidazole nitrogen N epsilon 2 of His57 leading to the inactivated enzyme (bis-adduct form).

Azetidines↗
PubMed1999

In vivo positron emission tomography studies on the novel nicotinic receptor agonist [11C]MPA compared with [11C]ABT-418 and (S)(-)[11C]nicotine in rhesus monkeys.

The novel 11C-labeled nicotinic agonist (R,S)-1-[11C]methyl-2(3-pyridyl)azetidine ([11C]MPA) was evaluated as a positron emission tomography (PET) ligand for in vivo characterization of nicotinic acetylcholine receptors in the brain of Rhesus monkeys in comparison with the nicotinic ligands (S)-3-methyl-5-(1-[11C]methyl-2-pyrrolidinyl)isoxazol ([11C]ABT-418) and (S)(-)[11C]nicotine. The nicotinic receptor agonist [11C]MPA demonstrated rapid uptake into the brain to a similar extent as (S)(-) [11C]nicotine and [11C]ABT-418. When unlabeled (S)(-)nicotine (0.02 mg/kg) was administered 5 min before the radioactive tracers, the uptake of [11C]MPA was decreased by 25% in the thalamus, 19% in the temporal cortex, and 11% in the cerebellum, whereas an increase was found for the uptake of (S)(-)[11C]nicotine and [11C]ABT-418. This finding indicates specific binding of [11C]MPA to nicotinic receptors in the brain in a simple classical displacement study. [11C]MPA seems to be a more promising radiotracer than (S)(-)[11C]nicotine or [11C]ABT-418 for PET studies to characterize nicotinic receptors in the brain.

Animals↗
PubMed1993

Electrospray ionization mass spectrometry as a mechanistic tool: mass of human leucocyte elastase and a beta-lactam-derived E-I complex.

We have utilized liquid chromatography electrospray ionization mass spectrometry (ESI-MS) to probe the nature of the covalent E-I complex of human leucocyte elastase (HLE) and a beta-lactam. The mass spectrum of HLE isozyme 4 displayed one major and two minor components with masses of 25,202, 25,043, and 24,522 Da, respectively. Isozyme 3 displayed three components, with masses of 25,180, 24,030, and 24,523 Da. These data suggest that the isozymes differ in the type and not the content of carbohydrate. The minor components represent decreases in carbohydrate content. Inactivation of isozyme 4 with trans-4-(ethoxycarbonyl)-3-ethyl-1-[(4-nitrophenyl)sulfonyl]-azetidin -3-one increased the mass of the three components by that of the parent compound. Similar results were obtained with the mixture of HLE isozymes. These observations demonstrate that HLE does not catalyze the beta-elimination of p-nitrophenylsulfinate as Firestone et al. [(1990) Tetrahedron 46, 2255) suggested. In addition, it suggests that a "double hit" of both the active-site serine and histidine is not required to form a stable acyl-enzyme. Noncovalent complexes between HLE and either the tight-binding secretory leucoprotease inhibitor (SLPI) or a slow tight-binding peptide difluoroketone inhibitor were not observed by ESI-MS. SLPI displayed a mass of 11,710 Da in the absence and presence of HLE. These data demonstrate the utility of ESI-MS to probe the mechanism of inhibition of enzymes by mechanism-based inhibitors.

Anti-Bacterial Agents↗
PubMed1998

Mechanism of inhibition of LDL phospholipase A2 by monocyclic-beta-lactams. Burst kinetics and the effect of stereochemistry.

Investigation of the inhibition of LDL-associated phospholipase A2 by monocyclic beta-lactams has shown that LDL phospholipase A2 is capable of hydrolyzing monocyclic-beta-lactams by a mechanism which shares many similarities to the hydrolysis of beta-lactams by beta-lactamases. We believe that this is the first demonstration of a serine-dependent lipase being able to hydrolyze an amide bond. Although 4-(phenylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one, SB-216477, and its enantiomers are relatively modest covalent inactivators with kobs/[I] = 46 M-1 s-1 for the R enantiomer, analysis of the kinetics of inactivation and reactivation shows that these compounds act as slow-turnover substrates, presumably via an acylation-deacylation mechanism. The detection of a suprastoichiometric burst indicates that the pathway must be branched with the branching giving rise to the slow reactivation via a more stable covalent intermediate. Study of the two enantiomers of SB-216477 shows that LDL-associated phospholipase A2 is sensitive to the beta-lactam stereochemistry at C4. However, a common achiral intermediate is formed along the turnover pathway, and this must be at or immediately prior to the branch point.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2001

A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor.

Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the 6-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (1) as a potent antagonist of the GnRH receptor. A 10(4)-fold increase in in vitro binding affinity is observed for the GnRH receptor as compared to the initial screening lead. Compound 1 exhibits nanomolar binding activity and functional antagonism at the human receptor and is 7-fold less active at the rhesus receptor. Intravenous administration of compound 1 to rhesus monkeys results in a significant decrease of the serum levels of downstream hormones, luteinizing hormone (79% decrease in area under the curve) and testosterone (92% decrease in area under the curve), at a dose of 3 mg/kg. Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates.

Animals↗
PubMed2002

Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide (LSD).

Lysergic acid amides were prepared from (R,R)-(-)-, (S,S)-(+)-, and cis-2,4-dimethyl azetidine. The dimethylazetidine moiety is considered here to be a rigid analogue of diethylamine, and thus, the target compounds are all conformationally constrained analogues of the potent hallucinogenic agent, N,N-diethyllysergamide, LSD-25. Pharmacological evaluation showed that (S,S)-(+)-2,4-dimethylazetidine gave a lysergamide with the highest LSD-like behavioral activity in the rat two lever drug discrimination model that was slightly more potent than LSD itself. This same diastereomer also had the highest affinity and functional potency at the rat serotonin 5-HT(2A) receptor, the presumed target for hallucinogenic agents, and a receptor affinity profile in a panel of screens that was most similar to that of LSD itself. Both cis- and the (R,R)-trans-dimethylazetidines gave lysergamides that were less potent in all relevant assays. The finding that the S,S-dimethylazetidine gave a lysergamide with pharmacology most similar to LSD indicates that the N,N-diethyl groups of LSD optimally bind when they are oriented in a conformation distinct from that observed in the solid state by X-ray crystallography. The incorporation of isomeric dialkylazetidines into other biologically active molecules may be a useful strategy to model the active conformations of dialkylamines and dialkylamides.

3T3 Cells↗
PubMed2003

A novel antibacterial 8-chloroquinolone with a distorted orientation of the N1-(5-amino-2,4-difluorophenyl) group.

Fluoroquinolones represent a major class of antibacterial agents with great therapeutic potential. In this study, we designed m-aminophenyl groups as novel N-1 substituents of naphthyridones and quinolones. Among newly synthesized compounds, 7-(3-aminoazetidin-1-yl)-1-(5-amino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4) has extremely potent antibacterial activities against Gram (+) as well as Gram (-) bacteria. This compound is significantly more potent than trovafloxacin against clinical isolates: 30 times against Streptococcus pneumoniae and 128 times against methicillin resistant Staphylococcus aureus. The structure-activity relationship (SAR) study revealed that a limited combination of 1-(5-amino-2,4-difluorophenyl) group, 7-(azetidin-1-yl) group, and 8-Cl atom (or Br atom or Me group) gave potent antibacterial activity. An X-ray crystallographic study of a 7-(3-ethylaminoazetidin-1-yl)-8-chloro derivative demonstrated that the N-1 aromatic group was remarkably distorted out of the core quinolone plane by steric repulsion between the C-8 Cl atom and the N-1 substituent. Furthermore, a molecular modeling study of 4 and its analogues demonstrated that a highly distorted orientation was induced by a steric hindrance of the C-8 substituent, such as Cl, Br, or a methyl group. Thus, their highly strained conformation should be a key factor for the potent antibacterial activity.

Anti-Bacterial Agents↗
PubMed2005

From 1-acyl-beta-lactam human cytomegalovirus protease inhibitors to 1-benzyloxycarbonylazetidines with improved antiviral activity. A straightforward approach to convert covalent to noncovalent inhibitors.

Starting from the structure of known beta-lactam covalent human cytomegalovirus (HCMV) protease inhibitors and from the knowledge of the residues implicated in the active site of this enzyme, we designed a series of phenylalanine-derived 2-azetidinones bearing a 4-carboxylate moiety that could be apt for additional interactions with the guanidine group of the Arg165/Arg166 residues of the viral protease. Some compounds within this series showed anti-HCMV activity at 10-50 muM, but rather high toxicity. The presence of aromatic 1-acyl groups and a certain hydrophobic character in the region of the 4-carboxylate were stringent requirements for anti-HCMV activity. To go a step ahead into the search for effective HCMV medicines, we then envisaged a series of noncovalent inhibitors by simple deletion of the carbonyl group in the beta-lactam derivatives to provide the corresponding azetidines. This led to low micromolar inhibitors of HCMV replication, with 17 and 27 being particularly promising lead compounds for further investigation, although their toxicity still needs to be lowered.

Alanine↗