ABSTRACT
Results from a medicinal chemistry approach aimed at replacing the quinoline ring system in the potent and selective human neurokinin-3 (hNK-3) receptor antagonists 1-4 of general formula I are discussed. The data give further insight upon the potential NK-3 pharmacophore. In particular, it is highlighted that both the benzene-condensed ring and the quinoline nitrogen are crucial determinants for optimal binding affinity to the hNK-3 receptor. Some novel compounds maintained part of the binding affinity to the receptor (5, 6, 10 and 13) and compound 5, featuring the naphthalene ring system, appears to be suitable for further modifications; it offers the option to introduce electron-withdrawing groups at position 2 and 4, conferring on the ring an overall electron-deficiency similar to that of the quinoline.
Subject(s)
Quinolines/chemical synthesis , Quinolines/pharmacology , Receptors, Neurokinin-3/antagonists & inhibitors , Animals , Binding, Competitive/drug effects , CHO Cells , Cloning, Molecular , Cricetinae , Humans , Radioligand Assay , Structure-Activity RelationshipABSTRACT
The vacuolar H+-ATPase (V-ATPase), located on the ruffled border of the osteoclast, is a proton pump which is responsible for secreting the massive amounts of protons that are required for the bone resorption process. With the aim to identify new agents which are able to prevent the excessive bone resorption associated with osteoporosis, we have designed a novel class of potent and selective inhibitors of the osteoclast proton pump, starting from the structure of the specific V-ATPase inhibitor bafilomycin A1. Compounds 3a-d potently inhibited the V-ATPase in chicken osteoclast membranes (IC50 = 60-180 nM) and were able to prevent bone resorption by human osteoclasts in vitro at low-nanomolar concentrations. Notably, the EC50 of compound 3c in this assay was 45-fold lower than the concentration required for half-maximal inhibition of the V-ATPase from human kidney cortex. These results support the validity of the osteoclast proton pump as a useful molecular target to produce novel inhibitors of bone resorption, potentially useful as antiosteporotic agents.
Subject(s)
Bone Resorption/prevention & control , Bridged Bicyclo Compounds, Heterocyclic , Enzyme Inhibitors , Indoles , Osteoclasts/drug effects , Proton-Translocating ATPases/antagonists & inhibitors , Pyrimidines , Vacuoles/drug effects , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Membrane , Chickens , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Kidney Cortex/enzymology , Osteoclasts/enzymology , Osteoclasts/ultrastructure , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Tumor Cells, Cultured , Vacuoles/enzymologyABSTRACT
Optimisation of a novel series of osteoclast ATPase inhibitors led to (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6- pentamethylpiperidin-4-yl)-2,4-pentadienamide (1) that was the most potent compound in an in vitro osteoclast ATPase assay and in human bone resorption assays. Two of the possible geometric isomers have also been prepared and shown to be significantly less potent than 1.
