ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease

Author:

Sham Hing L.1,Kempf Dale J.1,Molla Akhteruzammen1,Marsh Kennan C.2,Kumar Gondi N.3,Chen Chih-Ming1,Kati Warren1,Stewart Kent4,Lal Ritu5,Hsu Ann5,Betebenner David1,Korneyeva Marina1,Vasavanonda Sudthida1,McDonald Edith2,Saldivar Ayda1,Wideburg Norm1,Chen Xiaoqi1,Niu Ping1,Park Chang4,Jayanti Venkata3,Grabowski Brian3,Granneman G. Richard5,Sun Eugene6,Japour Anthony J.6,Leonard John M.6,Plattner Jacob J.1,Norbeck Daniel W.1

Affiliation:

1. Departments of Infectious Diseases Research,1

2. Drug Analysis,2

3. Biotransformation,3

4. Structural Biology,4

5. Pharmacokinetics,5 and

6. Antiviral Venture,6 Abbott Laboratories, Abbott Park, Illinois 60064

Abstract

ABSTRACT The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease ( K i = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC 50 ], 0.006 to 0.017 μM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC 50 , ≤0.06 μM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC 50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC 50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference29 articles.

1. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease.;Cameron D. W.;Lancet,1998

2. In Vitro Selection and Characterization of Human Immunodeficiency Virus Type 1 Variants with Increased Resistance to ABT-378, a Novel Protease Inhibitor

3. Clumeck N. Clinical benefit of saquinavir (SQV) plus zalcitabine (ddC) plus zidovudine (ZDV) in untreated/minimally treated HIV-infected patients abstr. LB-4. Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy Toronto Canada. 1997 American Society for Microbiology Washington D.C

4. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease.;Danner S. A.;N. Engl. J. Med.,1995

5. Evaluation of methods for estimating the dissociation constant of tight binding inhibitors.;Greco W. R.;J. Biol. Chem.,1979

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