ABSTRACT
A series of 8-heteroarylthiomethyldipyridodiazepinone derivatives were prepared and evaluated for their antiviral profile against wild type virus and the important K103N/Y181C mutant as an indicator for broad activity. 2,6-Dimethylpyridine derivative 16 was found to have a good pharmacokinetic profile in spite of poor metabolic stability in rat liver microsomes.
Subject(s)
Anti-HIV Agents , Azepines , HIV Infections/drug therapy , HIV-1/drug effects , Nevirapine/chemical synthesis , Reverse Transcriptase Inhibitors , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacology , Azepines/chemical synthesis , Azepines/metabolism , Azepines/pharmacology , Drug Resistance, Viral , HIV Infections/virology , HIV Reverse Transcriptase/chemistry , HIV-1/enzymology , HIV-1/genetics , Humans , Metabolic Clearance Rate , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Mutation , Nevirapine/pharmacology , Pyridines/chemical synthesis , Pyridines/metabolism , Pyridines/pharmacology , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/metabolism , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development.
Subject(s)
Amides/chemistry , Renin/antagonists & inhibitors , Administration, Oral , Amides/pharmacokinetics , Amides/pharmacology , Animals , Biological Availability , Humans , Macaca fascicularis , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Renin/blood , Spectrophotometry, Infrared , Structure-Activity RelationshipABSTRACT
Renin inhibitors containing a 4,5- or a 3,5-dihydroxy-2-substituted-6-phenylhexanamide fragment at the P2-P3 sites have been prepared and evaluated. The four possible diastereomeric diols of the two series of inhibitors were synthesized to determine the optimal configuration of the carbinol centers for these replacements. The most potent inhibitors of each series, la and 2c have a molecular weight of only 503 and IC50 values of 23 and 20 nM in a human plasma renin assay at pH 6.0. Their very low aqueous solubility limited their further evaluation. The efficacy of these P2-P3 replacements is a result of their ability to maintain the important hydrogen-bonds with the enzyme. Due to conformational differences with the dipeptide, adjustment at the P2 side chain was required. These 4,5- and 3,5-dihydroxyhexanamide segments could be seen as novel N-terminal dipeptide replacements.