Otto MJ, Aldrich P, Grubb M, Shum L, Erickson-Viitanen S; International Conference on AIDS.
Int Conf AIDS.
1994 Aug 7-12; 10: 7 (abstract no. 320A).
DuPont Merck Pharmaceutical Co., Wilmington, DE.
OBJECTIVE: Previously we described the design and synthesis of a novel class of non-peptidyl inhibitors of HIV protease [SCIENCE 263:380-384 (1994)]. These cyclic urea inhibitors combined good antiviral potency with oral bioavailability in animals that was significantly enhanced relative to noncyclic inhibitors. Our objective was to discover cyclic urea inhibitors of HIV protease with improved oral pharmacokinetics and formulatability for development as oral therapeutics. METHODS: Antiviral activity was determined by standard methods in acutely infected cells. Pharmacokinetic parameters were evaluated after single p.o. or i.v. doses in rats and dogs. RESULTS: XM412 is a potent inhibitor of HIV protease (Ki = 0.3 nM) and of HIV-1 and HIV-2 replication in vitro. XM412 was equally effective against laboratory strains of HIV-1 and HIV-2 and against AZT-sensitive and resistant clinical isolates of HIV-1, with a mean IC90 against all HIV isolates tested of 0.12 +/- 0.08 microM. Single oral doses (10 mg/kg) of XM412 in solid or aqueous formulations produced peak plasma levels in dogs significantly higher than the antiviral IC90 (Cmax approximately 10x IC90) Plasma levels were maintained above the IC90 for > 16 hrs. Oral bioavailability (F%) for the rat was > 50% and was 50%-100% for the dog, depending on formulation and salt form. CONCLUSION: XM412 is a potent inhibitor of HIV replication in vitro with good oral pharmacokinetic properties in rats and dogs. Clinical trials with this new cyclic urea await completion of additional preclinical studies.
- Administration, Oral
- Antiviral Agents
- Biological Availability
- HIV Protease
- In Vitro
- antagonists & inhibitors
From Meeting Abstracts