First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.
Drug Discovery , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Mutant Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Dose-Response Relationship, Drug , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Models, Molecular , Molecular Structure , Mutation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.
HIV Integrase Inhibitors/chemical synthesis , HIV-1/drug effects , Heterocyclic Compounds, 3-Ring/chemical synthesis , Naphthyridines/chemical synthesis , Administration, Oral , Animals , Biological Availability , Cell Membrane Permeability , Cells, Cultured , Dogs , Drug Design , HIV Integrase Inhibitors/pharmacokinetics , HIV Integrase Inhibitors/pharmacology , HIV-1/enzymology , Hepatocytes/metabolism , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Liver/metabolism , Molecular Conformation , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Structure-Activity Relationship
HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the ß-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series.
HIV Integrase Inhibitors/chemistry , HIV Integrase/chemistry , HIV-1/enzymology , Hydroxamic Acids/chemistry , Indoles/chemistry , Administration, Oral , Animals , Dogs , HIV Integrase/metabolism , HIV Integrase Inhibitors/pharmacokinetics , HIV Integrase Inhibitors/toxicity , Half-Life , Hepatocytes/drug effects , Humans , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/toxicity , Structure-Activity Relationship
