Paracyclophanes: a novel class of water-soluble inhibitors of HIV proteinase.
A versatile synthesis of functionalized para- and metacyclophanes (macrocycles with one or more aromatic rings incorporated; ansa-compounds) has been developed. Cyclophanes constitute a novel building block for potent human immunodeficiency virus (HIV) protease inhibitors. The synthesis of the macrocyclic ring system was achieved by regio- and stereospecific ring opening of N-protected 4-amino-2,3-epoxy-5-phenylpentanoates with appropriate alpha, omega-diamines and consecutive ring closure under high dilution conditions. The resulting macrocyclic building blocks enabled further broad and flexible derivation. Paracyclophanes, containing oxyethylene substructures, were found to dissolve in phosphate-buffered saline at concentrations as high as 3 mg/mL at physiological pH. Several derivatives with Ki values lower than 10 nM and antiviral activities in the range of 15-50 nM have been obtained. The influence of the ring size and of the substitution pattern of the cyclophane moiety on enzyme inhibition, antiviral activity, and water solubility are discussed. Preliminary data on oral bioavailability in mice are given for selected compounds.
Ettmayer
P
P
Sandoz Forschungsinstitut Ges.m.b.H., Department of Antiretroviral Therapy, Vienna, Austria.
Billich
A
A
Hecht
P
P
Rosenwirth
B
B
Gstach
H
H
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D002478:Cells, Cultured; D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D004988:Ethers, Cyclic; D017320:HIV Protease Inhibitors; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; D016333:HIV Protease