ABSTRACT
This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.
Subject(s)
Antineoplastic Agents/chemistry , Benzimidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Aurora Kinases , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Cell Line, Tumor , Humans , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.
Subject(s)
Phenylurea Compounds/chemistry , Prodrugs/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Thiazoles/chemistry , Water/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Aurora Kinases , Male , Mice , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Protein Serine-Threonine Kinases/metabolism , Rats , Rats, Sprague-Dawley , Solubility , Thiazoles/pharmacokinetics , Thiazoles/pharmacologyABSTRACT
The pyridazinone ring system serves as an excellent scaffold for the diastereoselective preparation of novel cis-fused cyclopentapyridazinones utilizing the directed 5-exo radical cyclization approach. This overall approach was successfully employed in the preparation of a functionalized aza-spirocycle.
Subject(s)
Alkaloids/chemical synthesis , Pyridazines/chemical synthesis , Spiro Compounds/chemical synthesis , Alkaloids/chemistry , Aza Compounds/chemistry , Cyclization , Cyclopentanes/chemistry , Free Radicals/chemistry , Molecular Structure , Pyridazines/chemistry , Spiro Compounds/chemistry , StereoisomerismABSTRACT
This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.
