Joan A. Zugay

3'-Tetrahydrofuranylglycine as a novel, unnatural amino acid surrogate for asparagine in the design of inhibitors of the HIV protease

The blockade of the HIV protease has become a major target in the search for an effective therapy for AIDS.1 While many reports of potent HIV-1 inhibitors have appeared recently, the compound Ro 31-8959 remains the least selective for the HIV-1 and HIV-2 proteases.2 This property may result in reduced susceptibility to resistance since these represent the genetically most divergent strains of HIV presently known to exist.

Cycloalkylpiperazines as HIV-1 protease inhibitors: enhanced oral absorption

Abstract A series of HIV-1 protease inhibitors containing various acyclic or cyclic alkylpiperazine derivatives were prepared. They exhibit excellent potency in the enzyme inhibition assay and in a whole cell assay demonstrating the lowest CIC 95 IC 50 ratios observed in the hydroxyethylpiperazine class of inhibitors. Oral pharmacokinetic studies in dogs have been carried out on two compounds in this series and an excellent oral absorption profile was obtained for inhibitor 13 , which possesses a cyclopropylpiperazine unit.

Synthesis, antiviral activity, and bioavailability studies of γ-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.

Thiophene derivatives as extremely high affinity P3′ ligands for the hydroxyethylpiperazine class of HIV-1 protease inhibitors

Abstract A series of hydroxyethylpiperazine HIV-1 protease inhibitors containing various monocyclic or bicyclic thienylmethyl substituents as P3′ ligands were prepared. They were found to exhibit extremely high potency in the enzyme inhibition assay. These inhibitors also proved to be highly effective against viral spread in a whole cell assay. Some representative compounds in this series have been examined for oral bioavailability in dogs and the pharmacokinetic properties were found to be somewhat related to their aqueous solubilities.

A new hydroxyethylamine class of HIV-1 protease inhibitors with high antiviral potency and oral bioavailability

Abstract A new hydroxyethylamine class of inhibitors was designed combining features from our clinical candidate, L-735,524, along with small heterocyclic P 2 -ligands developed in these laboratories. Highly potent inhibitors possessing subnanomolar IC 50 s have been identified, which exhibit good antiviral potency in cell culture. L-738,872, a representative inhibitor in this class, showed 34% oral bioavailability in dogs.

Substituted alkylpyridines as P3′ ligands for the hydroxyethylpiperazine class of HIV-1 protease inhibitors: Improved pharmacokinetic profiles

Abstract As a systematic approach to develop HIV-1 protease inhibitors exhibiting desirable pharmacokinetic profiles, hydroxyethylpiperazine series of inhibitors containing various mono- or dialkyl-substituted pyridylmethyl groups have been examined. Very high enzyme inhibitory potency and antiviral activity in a whole cell assay were observed with these inhibitors and, when administered orally to dogs, selected compounds in this series exhibited prolonged half-lives compared to the non-substituted pyridylmethyl compound 1 .

Novel conformationally constrained HIV-1 protease inhibitors: rational design, enzyme inhibition, and X-ray structure of an enzyme-inhibtor complex

Abstract A new class of conformationally restricted HIV-1 protease inhibitors was designed based upon molecular modeling studies of known hydroxyethylamine (HEA) type inhibitors. The structure activity relationships for this series of compounds are discussed and an X-ray crystal complex between one of the inhibitors, L-707,897 and HIV-1 protease is presented.