[Cholesterol emboli].

The low oral bioavailability and rapid biliary excretion of peptide-derived HIV protease inhibitors have limited their utility as potential therapeutic agents. Our broad screening program to discover nonpeptidic HIV protease inhibitors had previously identified compound II (phenprocoumon, K(i) = 1 muM) as a lead template. Crystal structures of HIV protease complexes containing the peptide-derived inhibitor I (1-(naphthoxyacetyl)-L-histidyl-5(S)-amino-6-cyclohexyl-3 (R),4(R)-dihydroxy-2(R)-isopropylhexanoyl-L-isoleucine N-(2-pyridylmethyl)amide) and nonpeptidic inhibitors, such as phenprocoumon (compound II), provided a rational basis for the structure-based design of more active analogues. This investigation reports on the important finding of a carboxamide functionally appropriately added to the 4-hydroxycoumarin and the 4-hydroxy-2-pyrone templates which resulted in a new promising series of nonpeptidic HIV protease inhibitors with improved enzyme-binding affinity. The most active diastereomer of the carboxamide-containing compound XXIV inhibited HIV-1 protease with a K(i) value of 0.0014 muM. This research provides a new design direction for the discovery of more potent HIV protease inhibitors as potential therapeutic agents for the treatment of HIV infection.

4-Hydroxycoumarins↗

PubMed1995

[Use of anticoagulants during pregnancy].

Prolonged anticoagulant therapy may be indicated during pregnancy in patients with inborn diseases affecting haemostasis, mechanical heart valves, etc. A management scheme aimed at protecting both the mother and the foetus is presented on the basis of pharmacological data, the main series reported in the literature and the experience acquired at the Boucicaut hospital in Paris. Heparin should be used during the first trimester of pregnancy to avoid the teratogenic potential of antivitamin K drugs and to reduce the incidence of spontaneous abortions which increases in patients given oral anticoagulants. During the second and third trimester, antivitamin K drugs can be used more easily than heparin with no substantial increase in risk for the foetus. At delivery and during the immediate post partum period it is imperative to use a compound which does not cross the placental barrier (in order to avoid foetal hypocoagulation) and which has a short half-life. Heparin is therefore indicated again starting at eight months gestation. It is emphasized that despite careful management and follow-up by the co-ordinated efforts of cardiologists, obstetricians and the intensive care team haemorrhage occurs in 17% of the pregnant women given anticoagulants, particularly during the peri partum period.

4-Hydroxycoumarins↗

PubMed1995

Use of medium-sized cycloalkyl rings to enhance secondary binding: discovery of a new class of human immunodeficiency virus (HIV) protease inhibitors.

A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800 microM) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, Ki = 0.015 microM) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps).

4-Hydroxycoumarins↗