AEGiS-11IAC: The dihydropyrones: third-generation, non-peptidic HIV protease inhibitor development candidates.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

The dihydropyrones: third-generation, non-peptidic HIV protease inhibitor development candidates.

Int Conf AIDS 1996 Jul 7-12; 11:220 (abstract no. Tu.A.261)
Thaisrivongs S, Aristoff PA, Tarpley WG, Chong KT, Watenpaugh KD, Tomich PK, Dolak LA, Padbury GE, Schwende FJ, Zhao Z, Zipp GL, Kakuk TJ, Howe WJ, Romines KR, Romero DL, Chrusciel RA, Gammill RB; Pharmacia & Upjohn, Inc., Kalamazoo, MI. Fax: 616-385-7522. E-mail: sthaisri@pwinet.upj.com.

OBJECTIVE: Having introduced two generations of orally bioavailable, non-peptidic HIV protease inhibitors: U-96988 (in 1993) and U-103017 (in 1994) into phase I clinical trials, the aim was to optimize third-generation non-peptidic inhibitors with good PK property and oral bioavailability, and with significant improvement in antiviral potency, especially in the presence of plasma proteins.

METHODS: Crystal structures of a series inhibitors complexed with the HIV protease assisted the structure-based design effort. Analogues were assayed for inhibitory activity against purified HIV protease. Antiviral activity was assessed versus multiple HIV-1 laboratory and clinical isolates in several cell types. For PK studies, compounds were administered iv and orally to rats and dogs.

RESULTS: The third-generation non-peptidic compounds were identified in the dihydropyrone class: potent inhibitor of HIV protease (Ki less than 0.05 nM); high antiviral activity (IC50 = 50 nM in HIV-1IIIB infected H9 or MT4 cells; IC50 = 30 nM in HIV-1JRCSF infected PBMC; and IC90 (median) = 0.3 micromolar against a panel of ten AZT-resistant clinical HIV isolates in PBMC). In an assay medium with added 75% human plasma, there was an approximately half-a-log-unit increase in the IC50 value. After oral administration to dogs (Cmax = 26 micromolar at 10 mg/kg), the bioavailability was 40%.

CONCLUSION: Orally bioavailable third-generation, non-peptidic HIV protease inhibitors in the dihydropyrone class have been optimized with in vitro antiviral potency comparable to the peptide-derived inhibitors (saquinavir, indinavir, ritonavir). Very significantly, studies revealed that HIV-1 isolates highly resistant to ritonavir and broadly cross-resistant to peptide-derived inhibitors (saquinavir, indinavir, AG-1343) remained sensitive to these dihydropyrone inhibitors. Extensive preclinical studies are underway in order to initiate clinical trials in the second half of 1996.

Keywords: AEGIS, HIV Protease Inhibitors, HIV Protease, Indinavir, Saquinavir, Nelfinavir, Pyrones, HIV-1, Ritonavir, Zidovudine, Sulfonamides, Reverse Transcriptase Inhibitors, U 96988, U 103017, Dogs, Animal, Human, In Vitro, Rats, ICA11

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