ABSTRACT
A one-pot, Hantzsch ester-mediated Knoevenagel condensation-reduction reaction has been developed for alkylation of a wide range of substituted 2,4-quinoline diols and 2,4-pyridine diols with aldehydes. The process is operationally simple to perform, scalable, and provides highly useful C-3 alkylated quinoline and pyridine diols in yields of 58-92%. The alkylation products can be converted to 2,4-dihaloquinoline and pyridine substrates for further functionalization.
Subject(s)
Pyridines , Quinolines , Alcohols , Aldehydes , AlkylationABSTRACT
The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.
Subject(s)
Cyclic Nucleotide-Gated Cation Channels/antagonists & inhibitors , Drug Discovery , Indans/pharmacology , Animals , Cyclic Nucleotide-Gated Cation Channels/metabolism , Humans , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels , Indans/chemical synthesis , Indans/chemistry , Mice , Molecular Structure , Potassium Channels/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We describe a practical and scalable route to compound (Z)-1, a selective CCK1 receptor antagonist. Notable features of this concise route are (1) a regioselective construction of the pyrazole core through the reaction of an aryl hydrazine and an elaborated acetylenic ketone, (2) a Tf2O/pyridine mediated Z-selective dehydration of an α-hydroxyester, and (3) a stereoselective hydrolysis. The sequence is high-yielding and amenable for large-scale synthesis.
Subject(s)
Chlorobenzenes/chemical synthesis , Dioxoles/chemical synthesis , Dioxoles/pharmacology , Hydrazines/chemistry , Propionates/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Chlorobenzenes/chemistry , Dioxoles/chemistry , Hydrolysis , Ketones/chemistry , Molecular Structure , Propionates/chemistry , Pyrazoles/chemical synthesis , StereoisomerismABSTRACT
Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
Subject(s)
Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Animals , Ether-A-Go-Go Potassium Channels/drug effects , Histamine H3 Antagonists/pharmacokinetics , Indicators and Reagents , Indoles/pharmacokinetics , Isomerism , Models, Molecular , Rats , Structure-Activity Relationship , Thiophenes/pharmacokineticsABSTRACT
In a recent paper, [Arienti, K. L.; Brunmark, A.; Axe, F. U.; McClure, K. M.; Lee, A.; Blevitt, J.; Neff, D. K.; Huang, L.; Crawford, S.; Chennagiri, R. P.; Karlsson, L.; Brietenbucher, J. G. J. Med. Chem.2005, 48, 1873], we described the discovery of a class of benzimidazole chk2 kinase inhibitors, exemplified by compound 1, which had radio-protective effects in human T-cells subjected to ionizing radiation. Here, a series of non-benzimidazole analogs intended to define the scope of the SAR about this new series of inhibitor, and allow for refinement of the binding model of these compounds to the chk2 kinase is described.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Checkpoint Kinase 2 , Models, Molecular , Protein Kinase Inhibitors/pharmacology , Radiation-Protective Agents/chemistry , Radiation-Protective Agents/pharmacology , Structure-Activity RelationshipABSTRACT
Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.
