ABSTRACT
The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Drug Discovery , Methylamines/chemical synthesis , Methylamines/pharmacokinetics , Adamantane/analogs & derivatives , Adamantane/chemistry , Adamantane/pharmacology , Administration, Oral , Animals , Caco-2 Cells , Crystallography, X-Ray , Cyclization , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Methylamines/chemistry , Methylamines/pharmacology , Molecular Structure , Nitriles/chemistry , Nitriles/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Rats , Sitagliptin Phosphate , Triazoles/chemistry , Triazoles/pharmacology , VildagliptinABSTRACT
Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90alpha N-terminal domain complexed with the purine-based inhibitor, PU3, and analogs with enhanced potency both in enzyme and cell-based assays. The compounds induce upregulation of HSP70 and downregulation of the known HSP90 client proteins Raf-1, CDK4, and ErbB2, confirming that the molecules inhibit cell growth by a mechanism dependent on HSP90 inhibition. We have also determined the first structure of the N-terminal domain of HSP90beta, complexed with PU3. The structures allow a detailed rationale to be developed for the observed affinity of the PU3 class of compounds for HSP90 and also provide a structural framework for design of compounds with improved binding affinity and drug-like properties.
Subject(s)
Adenine/analogs & derivatives , Adenine/chemistry , Adenosine Triphosphatases/antagonists & inhibitors , Anisoles/chemistry , Enzyme Inhibitors/chemistry , HSP90 Heat-Shock Proteins/chemistry , Purines/chemistry , Adenine/metabolism , Adenine/pharmacology , Anisoles/metabolism , Anisoles/pharmacology , Binding Sites , Cell Division/drug effects , Drug Evaluation, Preclinical , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Humans , Ligands , Models, Molecular , Molecular Structure , Protein Isoforms , Protein Structure, Tertiary , Purines/metabolism , Purines/pharmacology , Structure-Activity RelationshipABSTRACT
Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.
Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Binding Sites , Crystallography, X-Ray , Heterocyclic Compounds, 2-Ring/chemistry , Humans , Models, Molecular , Molecular Structure , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
Information from X-ray crystal structures of Hsp90 inhibitors bound to the human Hsp90 molecular chaperone was used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as novel inhibitors of Hsp90. Accessing an extra interaction with the protein via Phe138 gave a significant increase in binding potency compared to similar analogues that do not make this interaction.
Subject(s)
Amides/chemistry , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Pyrazoles/chemistry , Amides/pharmacology , Crystallography, X-Ray , Drug Design , Humans , Molecular Structure , Oxamic Acid/chemistry , Pyrazoles/pharmacologyABSTRACT
Multiple co-crystal structures of an adenine-based series of inhibitors bound to the molecular chaperone Hsp90 have been determined. These structures explain the observed SAR for previously described compounds and new compounds, which possess up to 8-fold improved potency against the isolated enzyme. Anti-tumour cell potency and mechanism of action data is also described for the most potent compounds. These data should enable the design of more potent Hsp90 inhibitors.