ABSTRACT
Initial evaluation of a series 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines revealed a C(1') carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1') carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine template.
Subject(s)
Acids/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Pyrroles/chemistryABSTRACT
The SAR of C5' functional groups with terminal basic amines at the C6 aniline of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines is reported. Examples demonstrate potent inhibition of IGF-1R with 1000-fold selectivity over JNK1 and 3 in enzymatic assays.
Subject(s)
MAP Kinase Kinase 4/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Models, Molecular , Pyrimidines/chemistry , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
The evaluation of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines as inhibitors of the IGF-1R (IGF-IR) receptor tyrosine kinase is reported. Examples demonstrate nanomolar potencies in in vitro enzyme and mechanistic cellular assays as well as promising in vivo pharmacokinetics in rat.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Animals , Drug Discovery , Models, Molecular , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/chemistry , RatsABSTRACT
A synthetic route to bisanilino-1H-pyrrolo[2,3-d]pyrimidines has been discovered, wherein the C(6)-chloride reactivity is necessarily enhanced via reversible acid-catalyzed internal activation of the pyrimidine ring by a C(1')-carboxamide moiety. Subsequent selective nucleophilic displacements at C(6) and C(1') constitute a one-pot tandem protocol for the rapid assembly of bisanilino-1H-pyrrolo[2,3-d]pyrimidines.
Subject(s)
Amides/chemistry , Chemistry, Organic/methods , Pyrimidines/chemistry , Pyrroles/chemistry , Carbon/chemistry , Catalysis , Chlorides/chemistry , Drug Design , Models, ChemicalABSTRACT
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
Subject(s)
17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , 17-Hydroxysteroid Dehydrogenases/metabolism , Animals , Cell Line , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Macaca fascicularis , Pyrrolidinones/chemical synthesis , Rats , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesisABSTRACT
4,5-Disubstituted cis-pyrrolidinones were investigated as inhibitors of type II 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Early structure-activity relationship patterns for this class of compounds are discussed.
Subject(s)
17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyrrolidinones/pharmacology , 17-Hydroxysteroid Dehydrogenases/metabolism , Enzyme Inhibitors/chemistry , Humans , Pyrrolidinones/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).