ABSTRACT
Structure-based led optimisation of orally active reversible Methionine Aminopeptidase-2 (MetAP-2) inhibitors utilising a 'molecular budget' medicinal chemistry strategy is described. The key physicochemical parameters of target molecules (cLogP, molecular size and H-bond donor count) were monitored through straightforward and intuitive use of atom count and distribution. The balance between structure-based design and an awareness of the physicochemical properties of the compounds synthesised enabled the rapid identification of a potent molecule with good oral pharmacokinetic (PK) characteristics by making fewer, higher quality compounds. The resulting candidate quality molecule was validated in a mechanistic cellular assay and a rodent secondary immunisation model.
Subject(s)
Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Methionyl Aminopeptidases/antagonists & inhibitors , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Methionyl Aminopeptidases/metabolism , Molecular Structure , Structure-Activity RelationshipABSTRACT
A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology.
Subject(s)
Indazoles/chemistry , Receptors, Glucocorticoid/agonists , Sulfonamides/chemical synthesis , Binding Sites , Cell Line, Tumor , Computer Simulation , Drug Evaluation, Preclinical , Humans , Hydrophobic and Hydrophilic Interactions , Indazoles/chemical synthesis , Indazoles/pharmacology , Receptors, Glucocorticoid/metabolism , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
Aryl aminopyrazole amides capped with N-alkylbenzamides 13-16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxyethyl benzamides (e.g., 16e).
