ABSTRACT
The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.
Subject(s)
HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/chemistry , HIV-1/drug effects , Morpholines/chemical synthesis , Pyrimidinones/chemical synthesis , Administration, Oral , Animals , Biological Availability , Blood Proteins/metabolism , Cell Line, Tumor , Dogs , HIV Integrase Inhibitors/pharmacokinetics , HIV Integrase Inhibitors/pharmacology , HIV-1/enzymology , HIV-1/physiology , Humans , Macaca mulatta , Morpholines/pharmacokinetics , Morpholines/pharmacology , Protein Binding , Pyrimidinones/pharmacokinetics , Pyrimidinones/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
A novel and highly enantioselective Ru-catalyzed hydrogenation of N-sulfonylated-alpha-dehydroamino acids has been discovered and demonstrated in the synthesis of an anthrax lethal factor inhibitor (LFI). Herein, this methodology is used to prepare N-sulfonylated amino acids in up to 98% ee. This unprecedented hydrogenation uses a chiral Ru catalyst rather than Rh as typical for acylated dehydroamino acids and esters, and this work reports the first asymmetric hydrogenation of a tetrasubstituted dehydroamino acid derivative using a Ru catalyst. [reaction: see text]
Subject(s)
Amino Acids/chemical synthesis , Bacterial Toxins/antagonists & inhibitors , Ruthenium/chemistry , Amino Acids/chemistry , Amino Acids/pharmacology , Antigens, Bacterial , Bacillus anthracis/chemistry , Bacillus anthracis/pathogenicity , Catalysis , Hydrogenation , StereoisomerismABSTRACT
Pure (Z)-enamines readily prepared from beta-ketoesters and amides using (S)-phenylglycine amide were hydrogenated with very high diastereoselectivities (up to 200:1) using heterogeneous catalysis. Hydrogenolytic cleavage of the (S)-phenylglycine amide afforded the corresponding chiral beta-aminoesters and amides. The high geometrical purity of the (Z)-enamine and a simple activation procedure for the PtO2 catalyst are essential in achieving high selectivity.
