ABSTRACT
N-substituted azaindoles were discovered as potent pan-PIM inhibitors. Lead optimization, guided by structure and focused on physico-chemical properties allowed us to solve inherent hERG and permeability liabilities, and provided compound 27, which subsequently impacted KG-1 tumor growth in a mouse model.
Subject(s)
Antineoplastic Agents/pharmacology , Aza Compounds/pharmacology , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Aza Compounds/chemical synthesis , Aza Compounds/metabolism , Cell Line, Tumor , Crystallography, X-Ray , Humans , Indoles/chemical synthesis , Indoles/metabolism , Mice , Piperidines/chemical synthesis , Piperidines/metabolism , Piperidines/pharmacology , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Rats , Stereoisomerism , Xenograft Model Antitumor AssaysABSTRACT
N-substituted azaindoles were discovered as promising pan-PIM inhibitors. Lead optimization is described en route toward the identification of a clinical candidate. Modulation of physico-chemical properties allowed to solve inherent hERG and permeability liabilities. Compound 17 showed tumor growth inhibition in a KG1 tumor-bearing mouse model.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indoles/administration & dosage , Indoles/chemistry , Mice , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-pim-1/metabolism , Rats , Structure-Activity RelationshipABSTRACT
N-Substituted azaindoles have been discovered as pan-PIM kinase inhibitors. Initial SAR, early ADME and PK/PD data of a series of compounds is described and led to the identification of promising pan-PIM inhibitors which validated our interest in the 7-azaindole scaffold and led us to pursue the identification of a clinical candidate.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/metabolism , Animals , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Half-Life , Humans , Indoles/metabolism , Inhibitory Concentration 50 , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins c-pim-1/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Herein, we report a novel and general method, lead optimization attrition analysis (LOAA), to benchmark two distinct small-molecule lead series using a relatively unbiased, simple technique and commercially available software. We illustrate this approach with data collected during lead optimization of two independent oncology programs as a case study. Easily generated graphics and attrition curves enabled us to calibrate progress and support go/no go decisions on each program. We believe that this data-driven technique could be used broadly by medicinal chemists and management to guide strategic decisions during drug discovery.
Subject(s)
Algorithms , Antineoplastic Agents/pharmacology , Chemistry, Pharmaceutical/methods , Decision Support Techniques , Drug Discovery/methods , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/toxicity , Biological Assay , Humans , Models, Biological , Models, Statistical , SoftwareABSTRACT
A regiocontrolled synthesis of 3,4-disubstituted pyrrole-2-carboxaldehydes was completed in two steps from acyclic starting materials. A Barton-Zard pyrrole synthesis between N-methoxy-N-methyl-2-isocyanoacetamide and alpha-nitroalkenes or beta-nitroacetates provided N-methoxy-N-methyl pyrrole-2-carboxamides (pyrrole Weinreb amides), which were converted into the corresponding pyrrole-2-carboxaldehydes by treatment with lithium aluminum hydride. A regioselective oxidation of the pyrrole-2-carboxaldehydes gave the corresponding 3,4-disubstituted 3-pyrrolin-2-ones.
