ABSTRACT
N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11ß-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11ß-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Aminopyridines/pharmacokinetics , Sulfonamides/pharmacokinetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Aminopyridines/chemistry , Aminopyridines/pharmacology , Glutathione/pharmacokinetics , HEK293 Cells , Humans , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
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.
Subject(s)
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 RelationshipABSTRACT
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.
Subject(s)
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 RelationshipABSTRACT
HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication. Recently, HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Herein, we report the discovery of azaindole carboxylic acids and azaindole hydroxamic acids as potent inhibitors of the HIV-1 IN enzyme and their structure-activity relationships. Several 4-fluorobenzyl substituted azaindole hydroxamic acids showed potent antiviral activities in cell-based assays and offered a structurally simple scaffold for the development of novel HIV-1 IN inhibitors.
Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , HIV-1/enzymology , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Drug Evaluation, Preclinical , HIV Integrase Inhibitors/chemical synthesis , HIV-1/drug effects , Hydroxamic Acids/chemical synthesis , Inhibitory Concentration 50 , Ligands , Magnesium/metabolism , Picolines/chemistryABSTRACT
The Golden Triangle is a visualization tool developed from in vitro permeability, in vitro clearance and computational data designed to aid medicinal chemists in achieving metabolically stable, permeable and potent drug candidates. Classifying compounds as permeable and stable and plotting molecular weight (MW) versus octanol:buffer (pH 7.4) distribution coefficients (logD) or estimated octanol:buffer (pH 7.4) distribution coefficients (elogD) reveals useful trends. Analysis of at least two orthogonal trends, such as permeability and clearance, can be extremely effective in balancing and optimizing multiple properties. In addition, molecular weight and logD impact potency-efficiency calculations, allowing potency, clearance and permeability to be optimized simultaneously.
