ABSTRACT
ß-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C ß-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C ß-lactamases in vitro. It effectively restored imipenem's activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.
Subject(s)
Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , Cilastatin/chemistry , Drug Discovery , Enzyme Inhibitors/chemistry , Imipenem/chemistry , beta-Lactamase Inhibitors , Cilastatin/pharmacology , Cilastatin, Imipenem Drug Combination , Crystallography, X-Ray , Drug Combinations , Drug Resistance, Bacterial/drug effects , Imipenem/pharmacology , Inhibitory Concentration 50 , Klebsiella/drug effects , Microbial Sensitivity Tests , Models, Biological , Pseudomonas/drug effects , Structure-Activity RelationshipABSTRACT
Thrombin is a serine protease that plays a key role in blood clotting. Pyrrolidine 1 is a potent thrombin inhibitor discovered at Merck several years ago. Seven analogs (2-8) of 1 in which the pyrrolidine core was replaced with various heterocycles were prepared and evaluated for activity against thrombin, clotting factors VIIa, IXa, Xa, and XIIa, and trypsin. The thiomorpholine analog 6 was the most active, essentially matching the thrombin inhibitory activity of 1 with slightly improved selectivity over trypsin.
Subject(s)
Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/pharmacology , Thrombin/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thrombin/metabolismABSTRACT
The bridged monobactam ß-lactamase inhibitor MK-8712 (1) effectively inhibits class C ß-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C ß-lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1.
Subject(s)
Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/chemistry , Monobactams/chemical synthesis , beta-Lactamase Inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Binding Sites , Computer Simulation , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imipenem/pharmacology , Microbial Sensitivity Tests , Monobactams/pharmacology , Protein Structure, Tertiary , Structure-Activity Relationship , beta-Lactamases/metabolismABSTRACT
Bridged monobactam beta-lactamase inhibitors were prepared and evaluated as potential partners for combination with imipenem to overcome class C beta-lactamase mediated resistance. The (S)-azepine analog 2 was found to be effective in both in vitro and in vivo assays and was selected for preclinical development.
Subject(s)
Carbapenems/chemistry , Drug Discovery/methods , Imipenem/chemistry , beta-Lactamase Inhibitors , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Carbapenems/pharmacology , Drug Combinations , Imipenem/pharmacology , Mice , Pseudomonas Infections/drug therapy , Pseudomonas Infections/enzymology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/physiology , Structure-Activity Relationship , beta-Lactam Resistance/drug effects , beta-Lactam Resistance/physiology , beta-Lactamases/metabolismABSTRACT
The disposition and metabolism of paraherquamide (PHQ), a potent and broad-spectrum anthelminthic, were examined in sheep, dogs, and gerbils. The metabolism of PHQ in these species was extensive and marked by significant species differences both in vitro and in vivo. In sheep and gerbils, PHQ metabolism occurs mainly at the pyrrolidine moiety, generating several metabolites that, for the most part, retained nematodicidal activity in vitro. In dogs, the dioxepene group was also extensively metabolized, ultimately resulting in formation of a catechol and loss of pharmacological activity. After oral administration of [3H]PHQ to intact sheep, gerbils, and dogs, the majority of the administered radioactivity was recovered in feces. Intact PHQ accounted for 0% (dogs) to approximately 30% (sheep and gerbils) of drug-related material in feces. A detailed investigation of the composition of the intestinal content of sheep indicated that a significant amount of the dose was still present in the rumen 24 h after dose and that PHQ underwent significant dehydration in the cecum. The oral pharmacokinetic parameters of PHQ in sheep and dogs suggest that its absorption is rapid in both species but that its apparent elimination rate is significantly higher in the dog (t(1/2) approximately 1.5 h) than it is in sheep (t(1/2) approximately 8.5 h). The short elimination half-life and the absence of PHQ or other active components in the dog gastrointestinal tract provide a potential explanation of the lack of efficacy of PHQ in this species.
Subject(s)
Indolizines/pharmacokinetics , Spiro Compounds/pharmacokinetics , Administration, Oral , Animals , Dogs , Feces/chemistry , Gerbillinae , Half-Life , Indolizines/administration & dosage , Sheep , Spiro Compounds/administration & dosage , TritiumABSTRACT
A series of androstene-3,5-diene derivatives were prepared. Despite lacking the C-3 hydroxyl previously believed necessary for ER activity, some of the analogs retained surprising affinity for ER-beta. For example, diene 4 retained excellent selectivity and potency as an ER-beta agonist and was more selective for ER-beta over the androgen receptor (AR).
Subject(s)
Androstadienes/chemical synthesis , Androstadienes/pharmacology , Estrogen Receptor beta/agonists , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Androstadienes/chemistry , Animals , Binding Sites/drug effects , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Receptors, Androgen/drug effects , Selective Estrogen Receptor Modulators/chemistryABSTRACT
A series of bridged androstenediol derivatives was prepared. The bridged compounds exhibited reduced ER-beta selectivity relative to uncyclized analogs.
Subject(s)
Androstenediols/chemical synthesis , Estrogen Receptor beta/antagonists & inhibitors , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Androstenediols/pharmacology , Cyclization , Estrogen Receptor beta/chemistry , Estrogen Receptor beta/metabolism , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Subject(s)
Androstenediol/analogs & derivatives , Androstenediol/pharmacology , Estrogen Receptor beta/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Androstenediol/chemical synthesis , Crystallography, X-Ray , Humans , Ligands , Models, Molecular , Molecular Conformation , Selective Estrogen Receptor Modulators/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.
Subject(s)
Estrogen Receptor alpha/antagonists & inhibitors , Oxathiins/chemistry , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Animals , Ligands , RatsABSTRACT
An optimized side chain for dihydrobenzoxathiin SERAMs was discovered and attached to four dihydrobenzoxathiin platforms. The novel SERAMs show exceptional estrogen antagonist activity in uterine tissue and an MCF-7 breast cancer cell assay.
Subject(s)
Oxathiins/chemical synthesis , Receptors, Estrogen/chemistry , Selective Estrogen Receptor Modulators/chemical synthesis , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Dose-Response Relationship, Drug , Estrogen Antagonists/chemical synthesis , Estrogen Antagonists/pharmacology , Female , Humans , Oxathiins/pharmacology , Rats , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Uterus/drug effects , Uterus/growth & developmentABSTRACT
The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).
Subject(s)
Chromans/chemistry , Chromans/pharmacology , Estrogen Receptor alpha/metabolism , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Animals , Binding Sites , Cell Line , Female , Gene Expression/drug effects , Humans , Ligands , Models, Chemical , Molecular Structure , Organ Size , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Uterus/drug effectsABSTRACT
A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
Subject(s)
Oxathiins/pharmacology , Pyrrolidines/chemistry , Receptors, Estrogen/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Ligands , Models, Molecular , Oxathiins/chemistry , Receptors, Estrogen/metabolismABSTRACT
A series of benzoxathiin SERAMs with bicyclic amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Ligands , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/metabolism , Animals , Bridged Bicyclo Compounds/pharmacology , Female , Kinetics , Models, Molecular , Molecular Conformation , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Uterus/drug effectsABSTRACT
A series of benzoxathiin SERAMs with heteroatom-substituted amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
Subject(s)
Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/metabolism , Animals , Female , Kinetics , Ligands , Models, Molecular , Molecular Conformation , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Uterus/drug effectsABSTRACT
A series of 2-phenylspiroindenediones was prepared. The spiroindenediones were found to be less active than the corresponding spiroindenes as estrogen receptor ligands and failed to demonstrate the receptor subtype selectivity that had been anticipated from molecular modeling.
Subject(s)
Indenes/chemistry , Indenes/metabolism , Models, Chemical , Receptors, Estrogen/metabolism , Spiro Compounds/chemistry , Spiro Compounds/metabolism , Binding Sites , Humans , Ligands , Models, Molecular , Protein BindingABSTRACT
A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to raloxifene (1) as an estrogen receptor ligand.
Subject(s)
Indenes/chemical synthesis , Indenes/pharmacology , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Alkylation , Animals , Borohydrides , Crystallography, X-Ray , Humans , In Vitro Techniques , Indicators and Reagents , Raloxifene Hydrochloride/pharmacology , Rats , Receptors, Estrogen/drug effects , Structure-Activity RelationshipABSTRACT
Raloxifene is a selective estrogen receptor modulator which is effective in the treatment of osteoporosis in postmenopausal women. We report herein that cytochrome P450 (P450)3A4 is inhibited by raloxifene in human liver microsomal incubations. The nature of the inhibition was irreversible and was NADPH- and preincubation time-dependent, with K(I) and k(inact) values estimated at 9.9 microM and 0.16 min(-1), respectively. The observed loss of P450 3A4 activity was attenuated partially by glutathione (GSH), implying the involvement of a reactive metabolite(s) in the inactivation process. Subsequently, GSH adducts of raloxifene were identified in incubations with human liver microsomes; substitution with GSH occurred at the 5- or 7-position of the benzothiophene moiety or at the 3'-position of the phenol ring, with the 7-glutathionyl derivative being most abundant based on LC/MS and NMR analyses. These adducts are postulated to derive from addition of GSH to raloxifene arene oxides followed by dehydration and aromatization. Alternatively, raloxifene may be oxidized to an extended quinone intermediate, which then is trapped by GSH conjugation. The bioactivation of raloxifene most likely is catalyzed by P450 3A4, since the formation of GSH adducts was almost abolished when liver microsomes were pretreated with ketoconazole or with an inhibitory anti-P450 3A4 IgG. The GSH adducts also were detected in incubations of raloxifene with rat or human hepatocytes, while the corresponding N-acetylcysteine adducts were identified in the bile and urine from rats treated orally with the drug at 5 mg/kg. Taken together, these data indicate that P450 3A4-mediated bioactivation of raloxifene in vitro is accompanied by loss of enzyme activity. The significance of these findings with respect to the clinical use of raloxifene remains to be determined.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Enzyme Inhibitors/metabolism , Raloxifene Hydrochloride/metabolism , Selective Estrogen Receptor Modulators/metabolism , Sulfhydryl Compounds/chemistry , Acetylcysteine/chemistry , Animals , Cytochrome P-450 CYP3A , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Gas Chromatography-Mass Spectrometry , Glutathione/chemistry , Hepatocytes/enzymology , Hepatocytes/metabolism , Humans , Magnetic Resonance Spectroscopy , Male , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Oxidation-Reduction , Raloxifene Hydrochloride/chemistry , Raloxifene Hydrochloride/pharmacology , Rats , Rats, Sprague-Dawley , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacologyABSTRACT
A series of G6-amino derivatives of a lipophilic vancomycin analogue was prepared. Antibacterial activity of the analogues was inversely proportional to the degree of substitution of the G6-nitrogen. The fully substituted (quaternary) analogues were essentially inactive against vanA phenotype VREF strains but retained substantial activity against other bacteria, a profile reminiscent of teicoplanin.
