ABSTRACT
Our efforts to optimize prototype opioid receptor-like 1 (ORL1) antagonist 1 led to the discovery of 4-{3-[(2R)-2,3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidine 10. 10 showed potent ORL1 antagonistic activity, excellent selectivity over other opioid receptors, and in vivo efficacy after oral dosing. Currently clinical trials of 10 are underway.
Subject(s)
Benzimidazoles/administration & dosage , Benzimidazoles/pharmacology , Narcotic Antagonists , Piperidines/administration & dosage , Piperidines/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Administration, Oral , Animals , Benzimidazoles/metabolism , Benzimidazoles/pharmacokinetics , CHO Cells , Cricetinae , Cricetulus , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Mice , Piperidines/metabolism , Piperidines/pharmacokinetics , Rats , Receptors, Opioid/metabolism , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
The synthesis and biological evaluation of new potent opioid receptor-like 1 antagonists are presented. A structure-activity relationship (SAR) study of arylpyrazole lead compound 1 obtained from library screening identified compound 31, (1S,3R)-N-{[1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1H-pyrazol-3-yl]methyl}-3-fluorocyclopentanamine, which exhibits high intrinsic potency and selectivity against other opioid receptors and hERG potassium channel.
Subject(s)
Cyclopentanes/chemistry , Narcotic Antagonists , Pyrazoles/chemistry , Cyclopentanes/chemical synthesis , Cyclopentanes/pharmacology , Drug Discovery , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, Opioid/metabolism , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
Structure-activity studies on benzimidazole lead 1 obtained from library screening led to the discovery of potent and selective ORL1 antagonist 28, 5-chloro-2-[(1-ethyl-1-methylpropyl)thio]-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1H-benzimidazole, which is structurally distinct from conventional non-peptide antagonists known to date.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Narcotic Antagonists , Benzimidazoles/chemistry , Combinatorial Chemistry Techniques , Humans , Molecular Structure , Receptors, Opioid , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
Inositol phosphorylceramide (IPC) synthase is a common and essential enzyme in fungi and plants, which catalyzes the transfer of phosphoinositol to the C-1 hydroxy of ceramide to produce IPC. This reaction is a key step in fungal sphingolipid biosynthesis, therefore the enzyme is a potential target for the development of nontoxic therapeutic antifungal agents. Natural products with a desired biological activity, aureobasidin A (AbA), khafrefungin, and galbonolide A, have been reported. AbA, a cyclic depsipeptide containing 8 amino acids and a hydroxyl acid, is a broad spectrum antifungal with strong activity against many pathogenic fungi such as Candida spp., Cryptococcus neoformans, and some Aspergillus spp. Khafrefungin, an aldonic acid ester with a C22 long alkyl chain, has antifungal activity against C. albicans, Cr. Neoformans, and Saccharomyces cerevisiae. Galbonolide A is a 14-membered macrolide with fungicidal activity against clinically important strains, and is especially potent against Cr. neoformans. These classes of natural products are potent and specific antifungal agents. We review current progress in the development of IPC synthase inhibitors with antifungal activities, and present structure-activity relationships (SAR), physicochemical and structural properties, and synthetic methodology for chemical modification.
Subject(s)
Antifungal Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hexosyltransferases/antagonists & inhibitors , Animals , Antifungal Agents/chemistry , Depsipeptides/chemistry , Depsipeptides/pharmacology , Enzyme Inhibitors/chemistry , Glycolipids/chemistry , Glycolipids/pharmacology , Humans , Lactones/chemistry , Lactones/pharmacology , Mycoses/drug therapy , Structure-Activity RelationshipABSTRACT
The development of an efficient synthetic method enabled multi-gram synthesis of a key intermediate, which is useful for the modification at the C6-functional group of galbonolide analogues. The structure of a key intermediate including a conjugated diene was afforded by Horner-Emmons reaction, alkylation of Weinreb amide with alkyl lithium and a subsequent Wittig reaction.
Subject(s)
Alkadienes/chemistry , Antifungal Agents/chemical synthesis , Lactones/chemical synthesis , Alkylation , Antifungal Agents/pharmacology , Fungi/drug effects , Lactones/pharmacology , Microbial Sensitivity TestsABSTRACT
Asymmetric total synthesis of benzene analogues of galbonolide, a 14-membered antifungal macrolide, possessing a benzene ring instead of a conjugated diene structure, was achieved starting from chiral 1-aryl-1-propanol obtained by enzyme-catalyzed kinetic resolution with high enantioselectivity. Representatively, a method for the introduction of a methylthio and chloride function at the vinyl position was also established. The resulting analogues unfortunately exhibited very little antifungal potency in comparison with galbonolide A.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Lactones/chemical synthesis , Lactones/pharmacology , Macrolides/chemical synthesis , Macrolides/pharmacology , Catalysis , Fungi/drug effects , Microbial Sensitivity Tests , Oxidation-Reduction , StereoisomerismABSTRACT
A series of novel galbonolide derivatives having a modified methyl enol ether moiety were prepared in total synthetic procedures and evaluated for their in vitro antifungal activities. The antifungal activity was labile to modification of the enol ether functionality and almost all of the modified compounds lacked the activity except for the analogue with an introduction of a methylthio group at the C-6 position, which retained a modest antifungal potency against Cryptococcus neoformans.
Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Hexosyltransferases/antagonists & inhibitors , Lactones/chemistry , Lactones/pharmacology , Cryptococcus neoformans/drug effects , Drug Design , Hexosyltransferases/metabolismABSTRACT
Structure--activity relationship studies of 1beta-methyl-2-[(3S,5R)-5-(4-aminomethylphenyl)pyrrolidin-3-ylthio]carbapenems, especially those pertaining to the relationship between antibacterial activity and side-chain structure were conducted. These studies suggested that the trans-(3S,5R)-5-phenylpyrrolidin-3-ylthio side-chain and the aminomethyl group at the 4-position of the phenyl ring play a key role in enhancing the antibacterial activity against the MRSA and Pseudomonas aeruginosa strains. In particular, the basicity of a substituent at the 4-position of the phenyl ring were shown to greatly contribute to the antibacterial activity against MRSA and methicillin-resistant Staphyloccocus epidermidis strains. In contrast, the amidine group was shown to lead to potent antibacterial activity against P. aeruginosa strains comparable to that of imipenem, however, a good correlation between the basicity of the 4-substituent and antipseudomonal activity was not observed. In conclusion, the 4-aminomethyl or methylaminomethyl group on the phenyl ring was the best substituent for antipseudomonal activity.
Subject(s)
Carbapenems/chemical synthesis , Pyrrolidines/chemical synthesis , Animals , Bacteria/drug effects , Carbapenems/pharmacokinetics , Carbapenems/pharmacology , Dipeptidases/metabolism , Drug Resistance, Bacterial , Drug Stability , Microbial Sensitivity Tests , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Structure-Activity Relationship , SwineABSTRACT
A (2R,4S)-trans-disubstituted pyrrolidine ring system was constructed by employing iodine-mediated oxidative cyclization of (1R)-N-[1-(4-bromophenyl)-3-butenyl]acetamide 3 as a key step. The resulting diastereomeric mixture of (2R)-2-aryl-4-acetoxypyrrolidine 4 was stereoselectively converted to the side-chain of a novel ultrabroad-spectrum carbapenem 1, via (2R,4R)-2-aryl-4-hydroxypyrrolidine 7.