Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 22
Filter
Add more filters










Publication year range
1.
Bioorg Med Chem Lett ; 11(13): 1717-21, 2001 Jul 09.
Article in English | MEDLINE | ID: mdl-11425545

ABSTRACT

In response to the unexpectedly high affinity for opioid receptors observed in a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group, we have prepared the corresponding 3-CONH(2) analogues of morphine and naltrexone. High affinity (K(i)=34 and 1.7nM) for mu opioid receptors was seen, however, the new targets were 39- and 11-fold less potent than morphine and naltrexone, respectively.


Subject(s)
Amides/chemistry , Morphine Derivatives/chemistry , Naltrexone/analogs & derivatives , Receptors, Opioid/metabolism , Morphine Derivatives/chemical synthesis , Morphine Derivatives/metabolism , Naltrexone/chemical synthesis , Naltrexone/metabolism , Protein Binding
2.
Bioorg Med Chem Lett ; 11(5): 623-6, 2001 Mar 12.
Article in English | MEDLINE | ID: mdl-11266156

ABSTRACT

Unexpectedly high affinity for opioid receptors has been observed for a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group. For mu and kappa opioid receptors, the primary carboxamido derivative of cyclazocine ((+/-)-15) displayed high affinity (Ki=0.41 and 0.53 nM, respectively) nearly comparable to cyclazocine. A high enantiopreference ((2R,6R,11R)-) for binding was also observed. Compound (+/-)-15 also displayed potent antinociception activity in mice when administered icv.


Subject(s)
Amides/chemistry , Analgesics, Non-Narcotic/chemistry , Cyclazocine/chemistry , Narcotic Antagonists/chemistry , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Amides/metabolism , Analgesics, Non-Narcotic/chemical synthesis , Analgesics, Non-Narcotic/metabolism , Analgesics, Non-Narcotic/pharmacology , Animals , Cyclazocine/metabolism , Mice , Molecular Structure , Narcotic Antagonists/chemical synthesis , Narcotic Antagonists/metabolism , Narcotic Antagonists/pharmacology , Radioligand Assay , Structure-Activity Relationship
3.
J Med Chem ; 43(19): 3558-65, 2000 Sep 21.
Article in English | MEDLINE | ID: mdl-11000010

ABSTRACT

As part of an effort to identify novel opioid receptor interactive agents, we recently prepared a series of 8-(substituted)amino analogues of cyclazocine. We found the chiral 8-phenylamino (NHC(6)H(5)) cyclazocine derivative to have subnanomolar affinity for kappa opioid receptors and a 2-fold lower affinity for mu, opioid receptors. To determine if the benefits of (substituted)amino groups could be extended to the morphine core structure, we have made five novel 3-amino-3-desoxymorphine derivatives of general structure 5 where RR'N = H(2)N, CH(3)NH, (CH(3))(2)N, C(6)H(5)NH, and C(6)H(5)CH(2)NH. Relative to morphine, these derivatives had 38-273-fold, 11-41-fold, and 10-141-fold lower affinity for mu, delta, and kappa opioid receptors, respectively. Target compounds were made via Pd-catalyzed amination of a morphine 3-trifluoromethylsulfonate substrate where the 6-OH group was protected with a tert-butyldiphenylsilyl group. To make 6-tert-butyldiphenylsilyloxymorphine selectively, a new high-yield method was developed whereby morphine was bis-silylated using normal conditions followed by selective removal of the 3-tert-butyldiphenylsilyl group with catalytic tetrabutylammonium fluoride.


Subject(s)
Morphine Derivatives/chemical synthesis , Receptors, Opioid, delta/metabolism , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Adenylyl Cyclase Inhibitors , Animals , Brain/metabolism , Cell Line , Cyclazocine/analogs & derivatives , Cyclazocine/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Guinea Pigs , In Vitro Techniques , Morphine Derivatives/chemistry , Morphine Derivatives/metabolism , Radioligand Assay , Stereoisomerism
4.
Ann N Y Acad Sci ; 909: 1-11, 2000.
Article in English | MEDLINE | ID: mdl-10911920

ABSTRACT

Pentazocine and cyclazocine are two benzomorphans that were synthesized by the late Sydney Archer in 1962. These benzomorphans were synthesized as part of an effort to develop analgesics with little or no abuse potential. Pentazocine is used as an analgesic, often in individuals who have sever pain or in those who have drug-abuse problems. Cyclazocine is a low-liability analgesic and potential therapeutic for the treatment of drug abuse. The risk of drug dependence is lower with the benzomorphans, which usually act as partial agonists at the mu opioid receptor and as kappa agonists. In an attempt to synthesize analogs of cyclazocine with increased bioavailability and varying kappa agonist and partial mu agonist properties, a series of 8-amino derivatives of cyclazocine were synthesized. These compounds were characterized in radioligand binding assays for their affinity and selectivity for the mu, delta, and kappa opioid receptors. Mouse antinociceptive tests were used to characterize the agonist and antagonist properties of each compound at the mu, delta and kappa receptors.


Subject(s)
Analgesics/therapeutic use , Cyclazocine/therapeutic use , Pain/drug therapy , Pentazocine/therapeutic use , Substance-Related Disorders/drug therapy , Animals , Cyclazocine/analogs & derivatives , Male , Mice , Mice, Inbred ICR , Stereoisomerism , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 10(2): 183-7, 2000 Jan 17.
Article in English | MEDLINE | ID: mdl-10673107

ABSTRACT

Opioid binding affinities were assessed for a series of cyclazocine analogues where the prototypic 8-OH substituent of cyclazocine was replaced by amino and substituted-amino groups. For mu and kappa opioid receptors, secondary amine derivatives having the (2R,6R,11R)-configuration had the highest affinity. Most targets were efficiently synthesized from the triflate of cyclazocine or its enantiomers using Pd-catalyzed amination procedures.


Subject(s)
Analgesics/chemical synthesis , Benzeneacetamides , Cyclazocine/analogs & derivatives , Analgesics/pharmacology , Animals , Binding, Competitive , Brain/drug effects , Cyclazocine/chemistry , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/metabolism , Guinea Pigs , Molecular Structure , Naltrexone/analogs & derivatives , Naltrexone/metabolism , Narcotic Antagonists , Pyrrolidines/metabolism , Receptors, Opioid/agonists , Stereoisomerism , Structure-Activity Relationship
6.
J Med Chem ; 41(19): 3645-54, 1998 Sep 10.
Article in English | MEDLINE | ID: mdl-9733489

ABSTRACT

Two new series of antitumor agents, 4-aminomethylthioxanthenones (6-50) and 5-aminomethylbenzothiopyranoindazoles (51-61), are described and compared. Nearly all members of both series display excellent in vivo activity versus murine pancreatic adenocarcinoma 03 (Panc03) although there is little to distinguish the two series from each other. In both series there is no discernible relationship between structure and in vivo efficacy. Selected analogues were evaluated in vitro; all were observed to have moderate to strong DNA binding via intercalation. However, varying degrees of in vitro P388 cytotoxicity and topoisomerase II inhibition were seen. In general, those molecules which exhibited strong topoisomerase II inhibition were significantly more cytotoxic than those which did not. In both series, those derivatives (48-50, 60, and 61) having a phenolic hydroxy substitution exhibited the most potent P388 cytotoxicity and topoisomerase II inhibition.


Subject(s)
Antineoplastic Agents , Enzyme Inhibitors , Indazoles , Pyrans , Thioxanthenes , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , DNA, Neoplasm/metabolism , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Indazoles/pharmacology , Intercalating Agents/chemical synthesis , Intercalating Agents/chemistry , Intercalating Agents/pharmacology , Leukemia P388/pathology , Mice , Neoplasm Transplantation , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacology , Structure-Activity Relationship , Thioxanthenes/chemical synthesis , Thioxanthenes/chemistry , Thioxanthenes/pharmacology , Topoisomerase II Inhibitors , Tumor Cells, Cultured
7.
Drug Des Discov ; 15(1): 25-38, 1997 May.
Article in English | MEDLINE | ID: mdl-9332829

ABSTRACT

Novel antiherpetic 3-quinolinecarboxamides were discovered as part of a drug discovery program at Sterling Winthrop Inc. A major goal of this research was to identify novel non-nucleoside agents possessing activity against acyclovir resistant herpes simplex virus. From screening compound libraries in an HSV-2 plaque reduction assay, 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (1) emerged as an attractive lead structure. By modifying the quinoline ring at the 1-, 2-, 3-, 4-, and 7-positions, analogues were identified that have up to 5-fold increased in vitro potency relative to acyclovir. In a single dose mouse model of infection the 1-(4-FC6H4) analogue 17, one of the most potent derivatives in vitro, displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple dose regimen, however, it was 2-fold less potent. Mechanism of action studies indicate that these new compounds interact with a different, as yet undefined, molecular target than acyclovir.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Acyclovir/pharmacology , Animals , Antiviral Agents/chemical synthesis , Chlorocebus aethiops , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Herpesvirus 2, Human/drug effects , Humans , Mice , Quinolines/chemical synthesis , Simplexvirus/drug effects , Structure-Activity Relationship , Vero Cells , Viral Plaque Assay
8.
J Med Chem ; 38(14): 2531-40, 1995 Jul 07.
Article in English | MEDLINE | ID: mdl-7629792

ABSTRACT

The palladium-catalyzed coupling of 3- and 4-(trialkylstannyl)pyridines with 7-bromo or 7-chloro 1-substituted 1,4-dihydro-4-oxo-3-quinolinecarboxylates has provided access to the corresponding 1-substituted 1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. The antibacterial activity of these derivatives was studied with the finding that the optimal 1- and 7-position substituents for Gram positive activity are cyclopropyl and 4-(2,6-dimethylpyridinyl), respectively. We find that for the fluorine-substituted derivatives studied, the position of the fluorine on the quinolone nucleus or the number of fluorine atoms does not seem to be important for good Gram positive activity. For 1-cyclopropyl 7-(2,6-dimethyl-4-pyridinyl) derivatives, the 6-fluoro 4a, 8-fluoro 10d, 6,8-difluoro 10b, and 5,6,8-trifluoro 8, all provided equal antibacterial activity against Staphylococcus aureus ATCC 29213. There is also a correlation between the substitution on the 7-(4-pyridinyl) group and the Gram positive activity, particularly for S. aureus, clearly indicating that the 2,6-dimethylpyridinyl group is optimal. The MIC50 value for the most potent agents in this study against S. aureus ATCC 29213 is 0.008 microgram/mL. By comparison, ciprofloxacin and aminopyrrolidine 28 gave values of 0.25 and 0.015 microgram/mL, respectively, against this organism.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Carboxylic Acids/chemical synthesis , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacillus/drug effects , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Enterococcus faecalis/drug effects , Pseudomonas aeruginosa/drug effects , Streptococcus pneumoniae/drug effects , Structure-Activity Relationship
9.
J Med Chem ; 38(14): 2541-5, 1995 Jul 07.
Article in English | MEDLINE | ID: mdl-7629793

ABSTRACT

Supported by the antiherpetic properties of 3-quinolinecarboxamides and the importance of the planar intramolecular H-bonded beta-keto amide pharmacophore, a series of novel conformationally rigid analogues that contain a heterocyclic bridge between the 3- and 4-positions of the quinoline ring have been evaluated. Two isoxazolo-fused derivatives 17 and 23 displayed good in vitro antiherpetic potency that was similar to that of 1, the 3-quinolinecarboxamide that served as the comparison structure for this study. The pyrazolo, pyrrolo, and pyrimido derivatives showed considerably less or no activity. In vitro activity did not translate to in vivo efficacy. For 17, the lack of in vivo activity is likely a consequence of insufficient plasma drug levels (both Cmax and duration) in mice relative to the MIC versus HSV-2.


Subject(s)
Antiviral Agents/chemistry , Herpesvirus 2, Human/drug effects , Quinolines/chemistry , Animals , Antiviral Agents/pharmacology , Disease Models, Animal , Herpes Genitalis/drug therapy , Herpesvirus 2, Human/growth & development , Magnetic Resonance Spectroscopy , Mice , Quinolines/pharmacology , Viral Plaque Assay
10.
Biochem Pharmacol ; 50(1): 111-22, 1995 Jun 29.
Article in English | MEDLINE | ID: mdl-7605336

ABSTRACT

(S)-10-(2,6-Dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H - pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid (WIN 58161) is an enantiomerically pure quinolone with outstanding bacterial topoisomerase II (DNA gyrase, EC 5.99.1.3) inhibitory and antibacterial activity. Unlike most quinolones, WIN 58161 also exhibits significant inhibitory activity against mammalian topoisomerase II (EC 5.99.1.3). DNA gyrase and topoisomerase II inhibitory activities are enantioselective. Consequently, WIN 58161 and its enantiomer (WIN 58161-2) provide useful tools to probe the contribution of topoisomerase II inhibition to the mechanism of cytotoxicity of quinolones and the potential utility of quinolone-topoisomerase II inhibitors as antitumor agents. WIN 58161 inhibited both highly purified Escherichia coli DNA gyrase and HeLa cell topoisomerase II by the promotion of enzyme-DNA covalent complexes. WIN 58161 did not bind stably to DNA via intercalation and did not enhance the formation of topoisomerase I (EC 5.99.1.2)-DNA covalent complexes. At drug concentrations that are cytotoxic to P388 murine leukemia cells, WIN 58161 promoted intracellular DNA single-strand breaks (SSBs) that exhibited the hallmarks of being mediated by topoisomerase. DNA fragments were complexed with protein, and SSBs were readily resealed at 37 degrees following drug removal. WIN 58161-2 was neither cytotoxic nor did it promote intracellular SSBs in P388. These observations suggest that the mechanism of cytotoxicity of WIN 58161 is predominantly, if not exclusively, a result of topoisomerase II inhibition. When studied in tumor-bearing mice, WIN 58161 exhibited a significant antitumor effect against each of five tumors tested, whereas neither toxicity nor antitumor activity was observed with WIN 58161-2. We conclude from these studies that WIN 58161 represents the prototype of a novel chemical class of topoisomerase II inhibitor with potential clinical utility in treating cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Quinolones/pharmacology , Animals , Drug Screening Assays, Antitumor , Humans , Mice , Topoisomerase II Inhibitors , Tumor Cells, Cultured
11.
Anticancer Drug Des ; 10(3): 251-76, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7748459

ABSTRACT

We have examined the DNA cleavage site specificity of human type II DNA topoisomerase in the presence of each of five novel quinolone derivatives. Each quinolone derivative inhibited the human enzyme, inducing double-strand breaks with a four-base stagger. Break sites generated in response to each derivative had a predominance of C in the 3'-terminal position. Consensus sequences derived for cleavage sites induced by each derivative were strikingly similar, not only at the 3'-terminal position, but also at additional positions on either side of the broken phosphodiester bond. Analysis of these consensus sequences yielded information about possible interactions of specific substituents on the quinolone derivatives with DNA and/or topoisomerase. Comparison of the quinolone-based consensus sequences with those derived for cleavage sites generated by the human type II topoisomerase in the presence of either m-AMSA or VM-26, or in the absence of drug, provided compelling evidence that DNA cleavage sites include two domains: one which interacts with drug and a second, larger domain which interacts with topoisomerase.


Subject(s)
DNA Topoisomerases, Type II/metabolism , DNA/metabolism , Quinolones/pharmacology , Amsacrine/pharmacology , Base Sequence , HeLa Cells , Humans , Hydrolysis , Molecular Sequence Data , Substrate Specificity , Teniposide/pharmacology , Topoisomerase II Inhibitors
12.
J Med Chem ; 36(19): 2801-9, 1993 Sep 17.
Article in English | MEDLINE | ID: mdl-8410993

ABSTRACT

1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-ox o-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 microM (VP-16; EC50 = 0.81 microM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.


Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Fluoroquinolones , Quinolones , Topoisomerase II Inhibitors , Animals , Anti-Infective Agents/chemistry , HeLa Cells/drug effects , Humans , Leukemia P388/drug therapy , Mice , Structure-Activity Relationship
13.
J Med Chem ; 36(11): 1580-96, 1993 May 28.
Article in English | MEDLINE | ID: mdl-8388470

ABSTRACT

A series of novel 3-quinolinecarboxamides that are structurally similar to the quinolone class of antibacterial agents possess excellent antiherpetic properties. By modifying the quinoline ring at the 1-, 2-, 3-, and 7-positions, analogues were identified that have up to 5-fold increased HSV-2 plaque-reduction potency relative to acyclovir. In a single-dose mouse model of infection, one of the most potent derivatives in vitro, 1-(4-fluorophenyl)-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarbo xamide (97), displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple-dose regimen, however, 97 was 2-fold less potent. In mice dosed orally with 97, sustained plasma drug levels were evident that may account for the high efficacy observed. The molecular mechanism of action of these agents is not known; however, based on in vitro studies with acyclovir resistant mutants, it is likely that the mechanism differs from that of acyclovir. In vitro plaque-reduction potency was not generally predictive of oral efficacy in mice. An X-ray crystal structure of 97 corroborated the assignment of structure and provided useful insights as to the effect of conformation on plaque-reduction potency.


Subject(s)
Antiviral Agents/chemical synthesis , Quinolines/chemical synthesis , Simplexvirus/drug effects , Acyclovir/pharmacology , Administration, Oral , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Chlorocebus aethiops , Drug Resistance, Microbial , Female , Herpes Simplex/drug therapy , Mice , Mice, Inbred ICR , Quinolines/administration & dosage , Quinolines/pharmacology , Structure-Activity Relationship , Vero Cells , Viral Plaque Assay
14.
J Med Chem ; 31(10): 2024-7, 1988 Oct.
Article in English | MEDLINE | ID: mdl-3172139

ABSTRACT

A series of novel N-[1-alkyl-4(1H)-pyridinylidene]alkylamine hydrohalides has been prepared and evaluated as inhibitors of dental plaque formation, in vitro. Several members of the series exhibited potency ca. 9-fold greater than that of chlorhexidine vs Streptococcus sobrinus 6715-13. The di-n-octyl analogue, 11 (pirtenidine), was found to be highly efficacious against several other oral plaque-forming microorganisms and is presently undergoing preclinical evaluation.


Subject(s)
Actinomyces/drug effects , Aminopyridines/pharmacology , Anti-Bacterial Agents , Dental Plaque/microbiology , Streptococcus/drug effects , Dental Plaque/prevention & control , Humans , Microbial Sensitivity Tests
15.
J Med Chem ; 31(9): 1694-7, 1988 Sep.
Article in English | MEDLINE | ID: mdl-2842501

ABSTRACT

A novel conformationally restricted 1-cyclopropylquinolone (1) that incorporates structural features of both ofloxacin and ciprofloxacin has been prepared. Compound 1 was found to be a DNA gyrase inhibitor having potency similar to ofloxacin but less than ciprofloxacin. The cellular inhibitory and in vivo antibacterial potencies of 1 were found to be less than those of the two reference agents.


Subject(s)
Oxazines/pharmacology , Topoisomerase II Inhibitors , Animals , Bacteroides/enzymology , Chemical Phenomena , Chemistry , Ciprofloxacin/pharmacology , Escherichia coli/enzymology , Mice , Ofloxacin , Oxazines/chemical synthesis , Pseudomonas aeruginosa/enzymology , Staphylococcus aureus/enzymology , Streptococcus/enzymology
16.
J Med Chem ; 30(8): 1482-9, 1987 Aug.
Article in English | MEDLINE | ID: mdl-3039138

ABSTRACT

A unique combination of alpha 2-adrenoreceptor antagonist and serotonin-selective reuptake inhibitory activities has been identified in a series of 2-substituted 4,5-dihydro-1H-imidazole derivatives. This combination of blocking activities has provided one of these derivatives, napamezole hydrochloride (2), with potential as an antidepressant. A discussion of the syntheses of these compounds includes a convenient method for the conversion of nitriles to imidazolines with ethylenediamine and trimethylaluminum.


Subject(s)
Antidepressive Agents , Imidazoles/pharmacology , Receptors, Adrenergic, alpha/drug effects , Serotonin/metabolism , Animals , Blepharoptosis/chemically induced , Brain/drug effects , Brain/metabolism , Chemical Phenomena , Chemistry , Dioxanes/metabolism , Dioxanes/pharmacology , Dopamine/metabolism , Idazoxan , Imidazoles/chemical synthesis , Imidazoles/metabolism , Male , Mice , Muscle Contraction/drug effects , Muscle, Smooth/physiology , Norepinephrine/metabolism , Rats , Rats, Inbred Strains , Receptors, Adrenergic, alpha/physiology , Structure-Activity Relationship , Tetrabenazine/antagonists & inhibitors , p-Chloroamphetamine/antagonists & inhibitors
17.
Antimicrob Agents Chemother ; 27(1): 4-10, 1985 Jan.
Article in English | MEDLINE | ID: mdl-3885845

ABSTRACT

WIN 49375 (amifloxacin) is a synthetic antibacterial agent of the quinolone class. It is similar in chemical structure to pefloxacin but differs by containing a methylamino, rather than an ethyl, substituent at the 1-N position. The activity of WIN 49375 in vitro was comparable to those of norfloxacin and pefloxacin against Enterobacteriaceae and generally greater than those of tobramycin and cefotaxime. WIN 49375 was more active in vitro than carbenicillin and mezlocillin against Pseudomonas aeruginosa isolates and showed moderate activity against Staphylococcus aureus, with MICs of less than or equal to 2 micrograms/ml. The in vitro activity of WIN 49375 was not markedly affected by the presence of human serum, the size of the bacterial inoculum, or changes in pH between 6 and 8. Against systemic, gram-negative bacterial infections in mice, WIN 49375 was generally less active than cefotaxime but more active than gentamicin. WIN 49548, the major piperazinyl-N-desmethyl metabolite of WIN 49375, was aa effective as the parent drug against experimental infections in mice when given parenterally. When administered orally, however, this metabolite was less potent than WIN 49375. WIN 49375 was highly active by the oral route, with 50% effective doses within two- to threefold of those obtained with parenteral medication.


Subject(s)
Anti-Bacterial Agents , Bacteria/drug effects , Ciprofloxacin/analogs & derivatives , Fluoroquinolones , Quinolines/pharmacology , Animals , Anti-Bacterial Agents/metabolism , Escherichia coli Infections/drug therapy , Female , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Quinolines/metabolism
18.
J Med Chem ; 27(9): 1103-8, 1984 Sep.
Article in English | MEDLINE | ID: mdl-6381730

ABSTRACT

A series of novel 3-quinolinecarboxylic acid derivatives have been prepared and their antibacterial activity evaluated. These derivatives are characterized by fluorine attached to the 6-position and substituted amino groups appended to the 1- and 7-positions. Structure-activity relationship studies indicate that antibacterial potency is greatest when the 1-substituent is methylamino and the 7-substituent is either 4-methyl-1-piperazinyl, 16, or 1-piperazinyl, 21. Derivatives 16 and 21, the 1-methylamino analogues of pefloxacin and norfloxacin, respectively, show comparable in vitro and in vivo antibacterial potency to these two known agents. The activity (vs. Escherichia coli Vogel) of 16 (amifloxacin) is the following: in vitro MIC (microgram/mL) = 0.25; in vivo (mice) PD50 (mg/kg) = 1.0 (po), 0.6 (sc).


Subject(s)
Anti-Bacterial Agents , Quinolines/chemical synthesis , Escherichia coli/drug effects , Quinolines/pharmacology , Structure-Activity Relationship
19.
J Med Chem ; 23(1): 71-4, 1980 Jan.
Article in English | MEDLINE | ID: mdl-7359514

ABSTRACT

The little compound 1a has been prepared and was found to be a strong, orally active agonist with narcotic--antagonist properties. 1a was prepared by two independent routes: (1) nitration of volazocine and subsequent reduction and (b) a sequence involving dissolving metal reduction of cyclazocine methyl ether, followed by oximination and Semmler--Wolff rearrangement. Several analogues were prepared and tested.


Subject(s)
Cyclazocine/analogs & derivatives , Analgesics/chemical synthesis , Animals , Dose-Response Relationship, Drug , Mice , Narcotic Antagonists/chemical synthesis , Rats , Reaction Time/drug effects , Structure-Activity Relationship , Time Factors
SELECTION OF CITATIONS
SEARCH DETAIL
...