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1.
Chemistry ; 24(39): 9957-9967, 2018 Jul 11.
Article in English | MEDLINE | ID: mdl-29939431

ABSTRACT

The intestinal disease shigellosis caused by Shigella bacteria affects over 120 million people annually. There is an urgent demand for new drugs as resistance against common antibiotics emerges. Bacterial tRNA-guanine transglycosylase (TGT) is a druggable target and controls the pathogenicity of Shigella flexneri. We report the synthesis of sugar-functionalized lin-benzoguanines addressing the ribose-33 pocket of TGT from Zymomonas mobilis. Ligand binding was analyzed by isothermal titration calorimetry and X-ray crystallography. Pocket occupancy was optimized by variation of size and protective groups of the sugars. The participation of a polycyclic water-cluster in the recognition of the sugar moiety was revealed. Acetonide-protected ribo- and psicofuranosyl derivatives are highly potent, benefiting from structural rigidity, good solubility, and metabolic stability. We conclude that sugar acetonides have a significant but not yet broadly recognized value in drug development.


Subject(s)
Guanine/chemistry , Pentosyltransferases/chemistry , RNA, Transfer/chemistry , Ribose/chemistry , Sugars/chemistry , Zymomonas/chemistry , Crystallography, X-Ray , Molecular Structure , Pentosyltransferases/metabolism , Protein Binding , Solvents
2.
ChemMedChem ; 11(19): 2216-2239, 2016 10 06.
Article in English | MEDLINE | ID: mdl-27629993

ABSTRACT

The modulation of pharmacologically relevant properties of N-alkyl-piperidine-2-carboxamides was studied by selective introduction of 1-3 fluorine atoms into the n-propyl and n-butyl side chains of the local anesthetics ropivacaine and levobupivacaine. The basicity modulation by nearby fluorine substituents is essentially additive and exhibits an exponential attenuation as a function of topological distance between fluorine and the basic center. The intrinsic lipophilicity of the neutral piperidine derivatives displays the characteristic response noted for partially fluorinated alkyl groups attached to neutral heteroaryl systems. However, basicity decrease by nearby fluorine substituents affects lipophilicities at neutral pH, so that all partially fluorinated derivatives are of similar or higher lipophilicity than their non-fluorinated parents. Aqueous solubilities were found to correlate inversely with lipophilicity with a significant contribution from crystal packing energies, as indicated by variations in melting point temperatures. All fluorinated derivatives were found to be somewhat more readily oxidized in human liver microsomes, the rates of degradation correlating with increasing lipophilicity. Because the piperidine-2-carboxamide core is chiral, pairs with enantiomeric N-alkyl groups are diastereomeric. While little response to such stereoisomerism was observed for basicity or lipophilicity, more pronounced variations were observed for melting point temperatures and oxidative degradation.


Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Dose-Response Relationship, Drug , Halogenation , Humans , Hydrophobic and Hydrophilic Interactions , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Piperidines/chemical synthesis , Piperidines/metabolism , Structure-Activity Relationship , Temperature
3.
J Med Chem ; 58(22): 9041-60, 2015 Nov 25.
Article in English | MEDLINE | ID: mdl-26523333

ABSTRACT

The synthesis of a collection of 3-substituted indole derivatives incorporating partially fluorinated n-propyl and n-butyl groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aqueous solubility, and metabolic stability. The experimental observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit molecular design in medicinal chemistry and, more broadly, in life as well as materials sciences.


Subject(s)
Drug Discovery/methods , Fluorine Compounds/chemical synthesis , Fluorine Compounds/pharmacology , Animals , Biotransformation , Chemistry, Physical , Drug Design , Fluorine Compounds/pharmacokinetics , Halogenation , Humans , In Vitro Techniques , Lipids/chemistry , Microsomes, Liver/metabolism , Protein Structure, Tertiary , Rats , Solubility , Structure-Activity Relationship , Thermodynamics
4.
Angew Chem Int Ed Engl ; 54(1): 349-54, 2015 Jan 02.
Article in English | MEDLINE | ID: mdl-25425560

ABSTRACT

The formal [2+2] cycloaddition-retroelectrocyclization (CA-RE) reactions between tetracyanoethylene (TCNE) and strained, electron-rich dibenzo-fused cyclooctynes were studied. The effect of ring strain on the reaction kinetics was quantified, revealing that the rates of cycloaddition using strained, cyclic alkynes are up to 5500 times greater at 298 K than those of reactions using unstrained alkynes. Cyclobutene reaction intermediates, as well as buta-1,3-diene products, were isolated and their structures were studied crystallographically. Isolation of a rare example of a chiral buta-1,3-diene that is optically active and configurationally stable at room temperature is reported. Computational studies on the enantiomerization pathway of the buta-1,3-diene products showed that the eight-membered ring inverts via a boat conformer in a ring-flip mechanism. In agreement with computed values, experimentally measured activation barriers of racemization in these compounds were found to be up to 26 kcal mol(-1) .

5.
Chemistry ; 21(1): 126-35, 2015 Jan 02.
Article in English | MEDLINE | ID: mdl-25483606

ABSTRACT

The enzyme tRNA-guanine transglycosylase has been identified as a drug target for the foodborne illness shigellosis. A key challenge in structure-based design for this enzyme is the filling of the polar ribose-34 pocket. Herein, we describe a novel series of ligands consisting of furanoside-appended lin-benzoguanines. They were designed to replace a conserved water cluster and differ by the functional groups at C(2) and C(3) of the furanosyl moiety being either OH or OMe. The unfavorable desolvation of Asp102 and Asp280, which are located close to the ribose-34 pocket, had a significant impact on binding affinity. While the enzyme has tRNA as its natural substrate, X-ray co-crystal structures revealed that the furanosyl moieties of the ligands are not accommodated in the tRNA ribose-34 site, but at the location of the adjacent phosphate group. A remarkable similarity of the position of the oxygen atoms in these two structures suggests furanosides as a potential phosphate isoster.


Subject(s)
Guanine/metabolism , Pentosyltransferases/metabolism , Phosphates/metabolism , Water/chemistry , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/metabolism , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Drug Design , Guanine/chemistry , Ligands , Molecular Conformation , Molecular Docking Simulation , Pentosyltransferases/chemistry , Phosphates/chemistry , Zymomonas/enzymology
7.
J Med Chem ; 53(12): 4603-14, 2010 Jun 24.
Article in English | MEDLINE | ID: mdl-20491477

ABSTRACT

The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.


Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Piperazines/chemical synthesis , Psychotropic Drugs/chemical synthesis , Schizophrenia/drug therapy , Sulfones/chemical synthesis , Animals , Brain/metabolism , CHO Cells , Cricetinae , Cricetulus , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Macaca fascicularis , Male , Mice , Microdialysis , Motor Activity/drug effects , Patch-Clamp Techniques , Piperazines/pharmacokinetics , Piperazines/pharmacology , Psychotropic Drugs/pharmacokinetics , Psychotropic Drugs/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Sulfones/pharmacokinetics , Sulfones/pharmacology
8.
ChemMedChem ; 2(8): 1100-15, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17530727

ABSTRACT

This review describes simple and useful concepts for predicting and tuning the pK(a) values of basic amine centers, a crucial step in the optimization of physical and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pK(a) values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chemistry. Next, the changes in pK(a) of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivatives are systematically analyzed, leading to the derivation of simple rules for pK(a) prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pK(a) predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.


Subject(s)
Amines/chemistry , Chemistry, Pharmaceutical , Antithrombins/chemistry , Drug Design , Information Storage and Retrieval
9.
Bioorg Med Chem Lett ; 16(16): 4311-5, 2006 Aug 15.
Article in English | MEDLINE | ID: mdl-16757170

ABSTRACT

A novel class of 4-aryl-8-(2-hydroxy-2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1- ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu-opioid receptor as well as the Nociceptin/Orphanin FQ peptide (NOP) receptor. In particular these novel compounds 4 as well as the 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one 3 show improved metabolic stability and pharmacokinetic profiles in rodents compared to previous triazaspiropiperidine series 1 and 2. We have also identified within these diazaspiropiperidine series a key relationship between reducing basicity of the piperidine nitrogen and reducing hERG affinity.


Subject(s)
Ether-A-Go-Go Potassium Channels/metabolism , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Opioid Peptides/chemistry , Animals , Chemistry, Pharmaceutical , Drug Design , Humans , Inhibitory Concentration 50 , Kinetics , Mice , Microsomes/metabolism , Models, Chemical , Peptides/chemistry , Protein Isoforms , Receptors, Opioid/chemistry , Nociceptin
10.
Bioorg Med Chem Lett ; 16(16): 4305-10, 2006 Aug 15.
Article in English | MEDLINE | ID: mdl-16762548

ABSTRACT

A novel class of 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor. A novel, straightforward and efficient synthetic strategy for the assembly of the target molecules is also presented.


Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Opioid Peptides/chemistry , Peptides/chemistry , G Protein-Coupled Inwardly-Rectifying Potassium Channels/chemistry , Humans , Inhibitory Concentration 50 , Models, Chemical , Protein Isoforms , Receptors, N-Methyl-D-Aspartate/chemistry , Receptors, Opioid/chemistry , Stereoisomerism , X-Rays , Nociceptin
11.
Bioorg Med Chem Lett ; 16(16): 4321-5, 2006 Aug 15.
Article in English | MEDLINE | ID: mdl-16762550

ABSTRACT

A novel class of 4-substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor. These molecules also exhibit superior pharmacological and pharmacokinetic parameters, relative to all GlyT1 inhibitors of the spiropiperidine family, culminating in the identification of 16b with an oral bioavailability of approximately 60%. In addition, a straightforward two-step procedure for the assembly of the target molecules is also presented.


Subject(s)
Glycine Plasma Membrane Transport Proteins/chemistry , Piperidines/pharmacology , Spiro Compounds/pharmacology , Administration, Oral , Animals , Ether-A-Go-Go Potassium Channels/metabolism , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Kinetics , Mice , Microsomes , Models, Chemical , Opioid Peptides/chemistry , Piperidines/chemistry , Protein Binding , Protein Isoforms , Spiro Compounds/chemistry , Temperature , Nociceptin
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