ABSTRACT
Preclinical investigations and early clinical trials suggest that FLT3 inhibitors are a viable therapy for acute myeloid leukemia. However, early clinical data have been underwhelming due to incomplete inhibition of FLT3. We have developed 3-phenyl-1H-5-pyrazolylamine as an efficient template for kinase inhibitors. Structure-activity relationships led to the discovery of sulfonamide, carbamate and urea series of FLT3 inhibitors. Previous studies showed that the sulfonamide 4 and carbamate 5 series were potent and selective FLT3 inhibitors with good in vivo efficacy. Herein, we describe the urea series, which we found to be potent inhibitors of FLT3 and VEGFR2. Some inhibited growth of FLT3-mutated MOLM-13 cells more strongly than the FLT3 inhibitors sorafenib (2) and ABT-869 (3). In preliminary in vivo toxicity studies of the four most active compounds, 10f was found to be the least toxic. A further in vivo efficacy study demonstrated that 10f achieved complete tumor regression in a higher proportion of MOLM-13 xenograft mice than 4 and 5 (70% vs 10% and 40%). These results show that compound 10f possesses improved pharmacologic and selectivity profiles and could be more effective than previously disclosed FLT3 inhibitors in the treatment of acute myeloid leukemia.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzamides/chemical synthesis , Benzamides/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Protein Kinase Inhibitors/chemical synthesis , Urea/analogs & derivatives , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzamides/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Discovery , Humans , Inhibitory Concentration 50 , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/pathology , Mice , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Sensitivity and Specificity , Structure-Activity Relationship , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacology , Xenograft Model Antitumor Assays , fms-Like Tyrosine Kinase 3/chemistryABSTRACT
A new class of FLT3 inhibitors has been identified based on the 3-phenyl-1H-5-pyrazolylamine scaffold. The structure-activity relationships led to the discovery of two carbamate series, and some potent compounds within these two series exhibited better growth inhibition of FLT3-mutated MOLM-13 cells than FLT3 inhibitors sorafenib (2) and ABT-869 (3). In particular, compound 8d exhibited the ability to regress tumors in mouse xenograft model using MOLM-13 cells.
Subject(s)
Amines/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Amines/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Mice , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Preclinical investigations and early clinical trial studies suggest that FLT3 inhibitors offer a viable therapy for acute myeloid leukemia. However, early clinical data for direct FLT3 inhibitors provided only modest results because of the failure to fully inhibit FLT3. We have designed and synthesized a novel class of 3-phenyl-1H-5-pyrazolylamine-derived compounds as FLT3 inhibitors which exhibit potent FLT3 inhibition and high selectivity toward different receptor tyrosine kinases. The structure-activity relationships led to the discovery of two series of FLT3 inhibitors, and some potent compounds within these two series exhibited comparable potency to FLT3 inhibitors sorafenib (3) and ABT-869 (4) in both wt-FLT3 enzyme inhibition and FLT3-ITD inhibition on cell growth (MOLM-13 and MV4;11 cells). In particular, the selected compound 12a exhibited the ability to regress tumors in mouse xenograft models using MOLM-13 and MV4;11 cells.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Sulfonamides/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzenesulfonates/chemistry , Benzenesulfonates/pharmacology , Cell Proliferation/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indazoles/chemistry , Indazoles/pharmacology , Mice , Molecular Structure , Niacinamide/analogs & derivatives , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemistry , Pyridines/pharmacology , Sorafenib , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure-activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC(50)>20 microM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Nitriles/chemical synthesis , Pyrrolidines/chemical synthesis , Administration, Oral , Amines , Animals , Biological Availability , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Inhibitory Concentration 50 , Nitriles/pharmacology , Pyrrolidines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A series of (2S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure-activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced chemical stability and excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. Compound 13f exhibited the ability to both significantly decrease the glucose excursion and inhibit plasma DPP-IV activity.
