ABSTRACT
A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.
Subject(s)
Carcinoma/drug therapy , Lung Neoplasms/drug therapy , Prodrugs/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrroles/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Triazines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Alanine/analogs & derivatives , Animals , Biological Availability , Cell Proliferation/drug effects , Clinical Trials, Phase II as Topic , Drug Design , Drug Evaluation, Preclinical , Humans , Intestines/drug effects , Liver/drug effects , Mice , Microsomes/drug effects , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Solubility , Stereoisomerism , Triazines/chemical synthesis , Triazines/chemistry , Water/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Substituted 3-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamides were identified as potent and selective inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2) kinase activity. The enzyme kinetics associated with the VEGFR-2 inhibition of 14 (Ki=49+/-9 nM) confirmed that the aminothiazole-based analogues are competitive with ATP. Analogue 14 demonstrated excellent kinase selectivity, favorable pharmacokinetic properties in multiple species, and robust in vivo efficacy in human lung and colon carcinoma xenograft models.
Subject(s)
Aminopyridines/chemical synthesis , Angiogenesis Inhibitors/chemical synthesis , Thiazoles/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Binding Sites , Cell Proliferation , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelium, Vascular/cytology , Humans , In Vitro Techniques , Macaca fascicularis , Mice , Mice, Nude , Models, Molecular , Rats , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Umbilical Veins/cytology , Vascular Endothelial Growth Factor Receptor-2/chemistry , Xenograft Model Antitumor AssaysABSTRACT
A series of substituted 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines was identified as potent and selective inhibitors of the tyrosine kinase activity of the growth factor receptors VEGFR-2 (Flk-1, KDR) and FGFR-1. The enzyme kinetics associated with the VEGFR-2 inhibition of compound 50 (K(i) = 52 +/- 3 nM) confirmed that the pyrrolo[2,1-f][1,2,4]triazine analogues are competitive with ATP. Several analogues demonstrated low-nanomolar inhibition of VEGF- and FGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation. Replacement of the C6-ester substituent of the pyrrolo[2,1-f][1,2,4]triazine core with heterocyclic bioisosteres, such as substituted 1,3,5-oxadiazoles, afforded compounds with excellent oral bioavailability in mice (i.e., 50 F(po) = 79%). Significant antitumor efficacy was observed with compounds 44, 49, and 50 against established L2987 human lung carcinoma xenografts implanted in athymic mice. A full account of the synthesis, structure-activity relationships, pharmacology, and pharmacokinetic properties of analogues within the series is presented.
