ABSTRACT
The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Lactams/chemical synthesis , Nitriles/chemical synthesis , Pyrrolidinones/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Binding, Competitive , Biological Availability , Cell Line, Transformed , Dogs , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Genes, ras , Imidazoles/chemistry , Imidazoles/pharmacology , Lactams/chemistry , Lactams/pharmacology , Mice , Mice, Transgenic , Models, Molecular , Neoplasms, Experimental/pathology , Nitriles/chemistry , Nitriles/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Radioligand Assay , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Structure-activity studies on the oxytocin antagonist 1 (L-371,257; Ki = 9.3 nM) have led to the identification of a related series of compounds containing an ortho-trifluoroethoxyphenylacetyl core which are orally bioavailable and have significantly improved potency in vitro and in vivo, e.g., compound 8 (L-374,943; Ki = 1.4 nM).
Subject(s)
Oxazines/chemical synthesis , Oxazines/pharmacokinetics , Oxytocin/antagonists & inhibitors , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Animals , Benzoxazines , Cell Line , Humans , Inhibitory Concentration 50 , Kinetics , Rats , Structure-Activity RelationshipABSTRACT
The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.
