Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.

Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.

Hear early: New Mexico's universal newborn hearing screening program.

Hear Early, New Mexico's newborn screening program, was established in 1996. Thirty-one of the state's 32 birthing hospitals participate in the Hear Early program that now screens 95% of New Mexico's 27, 500 births. The authors' experience in developing this statewide system is described and the critical components and the rationale behind this program are addressed. The development of Hear Early required input from a wide variety of professionals and consumers. Screening is only the first step in a comprehensive state program, which must also include assessment and intervention. Systems development, equipment issues, follow-up procedures, data management, and a tracking system are all pertinent factors. The various accomplishments and challenges that Hear Early has encountered are discussed.

Time- and dose-dependent pharmacokinetics of L-754,394, an HIV protease inhibitor, in rats, dogs and monkeys.

L-754,394 is a potent and specific inhibitor of the HIV-1 encoded protease that is essential for the maturation of the infectious virus. The drug exhibited dose-dependent kinetics in all species studied (rat, dog and monkey); the apparent clearance decreased when the dose was increased. However, the dose-dependency cannot be explained by Michaelis-Menten kinetics. L-754,394 in plasma declined log-linearly with time, but with an apparent half-life that increased with dose. The apparent terminal half-life of L-754,394 in rats increased from 20 min at 0.5 mg/kg i.v. to 118 min at 10 mg/kg i.v. Furthermore, L-754,394 exhibited time-dependent pharmacokinetics. After chronic i.v. doses for 7 days (1 mg/kg/dose/day), the apparent clearance of L-754,394 in rats decreased from 87 ml/min/kg after the first dose to 25 ml/min/kg after the last dose. Similar results were observed in dogs and monkeys. In vitro spectral studies indicated that approximately 40 to 60% of the content of cytochrome P-450 was inactivated when L-754,394 (10 microM) was incubated with rat, dog and monkey liver microsomes in the presence of NADPH. Little or no inactivation of cytochrome P-450 was observed when either NADPH or L-754,394 was omitted. In addition, L-754,394 selectively inhibited CYP 2C11-dependent testosterone 2 alpha- and 16 alpha-hydroxylase activity and CYP 3A1/2-dependent testosterone 6 beta-hydroxylase activity, but not CYP 2D1/2-dependent bufuralol 1'-hydroxylase activity nor CYP 1A2-dependent phenacetin O-deethylase activity in rat liver microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary schwannoma of the petrous apex.

We present two patients with primary petrous apex schwannoma. These tumors were centered on the petrous carotid artery and are thought to have originated from the deep petrosal nerve. This would account for the paucity of neurologic deficits in these patients. Imaging findings and surgical treatment of primary petrous apex schwannomas are discussed.

L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor.

A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with Ki values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1IIIb-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.

Synthesis, antiviral activity, and bioavailability studies of gamma-lactam derived HIV protease inhibitors.

Incorporation of a gamma-lactam in hydroxyethylene isosteres results in modest inhibitors of HIV-1 protease. Additional structural activity studies have produced significantly more potent inhibitors with the introduction of the trisubstituted cyclopentane (see compound 20) as the optimum substituent for the C-terminus. This new amino acid amide surrogate can be readily prepared in large scale from (R)-pulegone. Optimized compounds (36) and (60) are potent antiviral agents and are well absorbed (15-20%) in a dog model after oral administration.

L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor.

To date, numerous inhibitors of the human immunodeficiency virus type 1 protease have been reported, but few have been studied extensively in humans, primarily as a consequence of poor oral bioavailability in animal models. L-735,524 represents a class of human immunodeficiency virus type 1 protease inhibitors, termed hydroxyaminopentane amides, that incorporate a basic amine into the hydroxyethylene inhibitor backbone. L-735,524 is a potent inhibitor of virus replication in cell culture and inhibits the protease-mediated cleavage of the viral precursor polyproteins that results in the production of noninfectious progeny viral particles. The compound is effective against viruses resistant to reverse transcriptase inhibitors and is synergistically active when used in combination with reverse transcriptase inhibitors. Most importantly, L-735,524 exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals by using clinically acceptable formulations. Accordingly, the compound was selected for evaluation of safety and pharmacokinetic studies in humans.