Kenneth S. Su

POTENT, ORALLY BIOAVAILABLE HIV-1 PROTEASE INHIBITORS CONTAINING NONCODED D-AMINO ACIDS

Abstract Novel noncoded D-amino acids have been combined with decahydroisoquinoline, octahydrothienopyridine, and urea hydroxyethylamine isosteres to provide potent HIV-1 protease inhibitors with excellent HIV-1 antiviral activity. LY314613 shows a promising combination of potency and oral bioavailability. Trends in the SAR and comparisons to other isostere derivatives will be discussed.

Nasal Absorption of Enkephalins in Rats

In recent years, the possibility that the intranasal administration route might be useful for many compounds which are not absorbed orally has received a great deal of attention. For instance, the β-blocker propranolol (Hussain et al, 1979, 1980 a, b), the contraceptive agent progesterone (David et al, 1981; Hussain et al, 1981) and the anti-arrhythmic compound clofilium tosylate (Su et al, 1984) have been shown to be effectively absorbed via the intranasal route when compared to oral administration. These compounds undergo extensive degradation due to first-pass hepatic metabolism which can be minimized after nasal administration. For drugs which are poorly absorbed by the oral route such as sulbenicillin, cefazolin, and cephacetrile, it was demonstrated that the percent dose excreted in urine after nasal administration was nearly one-half of that after intramuscular administration (Hirai et al, 1981). The absorption of low molecular weight polypeptides, luteinising hormone-releasing hormone (LH-RH) and its analogues used as a contraceptive agent, was evaluated by the nasal route (Fink et al, 1974; Berquist et al, 1979; Gennser and Liedholm, 1974; London et al, 1973; Anik et al, 1984). Although the absorption efficiency by the nasal route was lower than the I.V. route for these polypeptides, the absorption was reproducible, and the advantage of non-parenteral route for such a compound was an important factor. Research has also been carried out on the nasal absorption of high molecular weight polypeptides such as insulin (Moses et al, 1983; Hirai et al, 1978, 1981 a,b), interferon (Greenberg et al, 1978; Harmon et al, 1976; 1977; Johnson et al, 1976) and growth hormone releasing factor (Evans et al, 1983).

Synthesis and pharmacokinetics of potent carbamate HIV-1 protease inhibitors containing novel high affinity hydroxyethylamine isosteres

Abstract Using the hydroxyethylamine isosteres 1 and 2 containing the novel cis-octahydrothienopyridine moiety, substantial enhancement of binding potencies for HIV-1 protease inhibitors which incorporate carbamate linked heterocyclic P2 ligands has been realized. This increase in binding has led to a very potent antiviral compound (LY326188). The pharmacokinetics of selected derivatives are detailed in this report.