HIV drug summary

This is a summary page for compounds under development or approved for treatment of HIV.

NIAID HIV/OI Searchable Chemical Database

VX-478; 141W94; Amprenavir; Agenerase®
	The sulfonamide amprenavir is a recently FDA-approved HIV protease inhibitor that came out of a program of rational drug design to be small, orally-bioavailable, and potent (1,4). X-ray crystal structure analysis of the protease-amprenavir complex reveals a very tight fit, with 397 A2 of solvent-accessible surface area being excluded upon complex formation (4). Significantly, hydrogen bonds are are seen between amprenavir and the active-site resident water molecule, as well as with the catalytic aspartate residue D25 (4). A hyperlink to the crystal structure (4) of the protease-amprenavir complex is available, as deposited with the Protein Data Bank (PDB) . In-vitro, amprenavir inhibits HIV-1 protease with Ki=0.60 nM, and HIV-2 protease only somewhat less well: Ki=19 nM (4). HIV-1 selected in-vitro to be highly-resistant to amprenavir express predominantly M46I, I47V and I50V mutations (3). Amprenavir shows significant binding (up to 90%) by plasma proteins such as a1-glycoprotein (5); however the effect of plasma proteins on EC90 is minimal (see below) as little net sequestration is seen, consistent with the observed fast off-rate for complex dissociation (100 s -1) (5). Pharmacokinetic data taken from HIV-infected patients orally dosed 1200 mg twice a day show excellent bioavailability: 20.7 µM maximum (Cmax)and 0.49 µM minimum (Cmin) serum levels (7), well above the EC90 levels seen against wild-type virus (see below). Rats given 10 mg/kg amprenavir show a T1/2~1 hour (8).
In-vitro Data Cell Strain EC50 IC50 Units TI Reference MT-4 HIV-1(IIIB) 0.054 89 µM 1600 6 PBL HIV-1(PRIM CLINICAL ISOLATE) 0.012-0.020 - µM - 1 MT-4 HIV-1(IIIB) 0.080 - µM - 2 MT-4 HIV-2(ZY) 0.340 - µM - 2 CEM-SS HIV-1(IIIB) 0.007;EC90=0.023 - µM - 3 CEM-SS HIV-1(IIIB P7(PR-L10F,I84V))* 0.5;EC90=0.880 - µM - 3 CEM-SS HIV-1(IIIB P8(PR-L10F,I50V))† 0.18;EC90=2.000 - µM - 3 CEM-SS HIV-1(IIIB P9(PR-L10F,M46I,I47V,I50V))‡ 1.500;EC90=3.400 - µM - 3 CEM-SS HIV-1(IIIB P10(PR-L10F,M46I,I47V,I50V,D60V))§ 1.100;EC90=4.000 - µM - 3 MT-4 HIV-1(HXB2)¶ 0.082 - µM - 3 MT-4 HIV-1(HXB2 (PR-L10F))¶ 0.080 - µM - 3 MT-4 HIV-1(HXB2 (PR-L10F,I84V))¶ 0.198 - µM - 3 MT-4 HIV-1(HXB2 (PR-M46I))¶ 0.086 - µM - 3 MT-4 HIV-1(HXB2 (PR-I47V))¶ 0.12 - µM - 3 MT-4 HIV-1(HXB2 (PR-I50V))¶ 0.177 - µM - 3 MT-4 HIV-1(HXB2 (PR-I84V))¶ 0.124 - µM - 3 MT-4 HIV-1(HXB2 (PR-M46I,I47V))¶ 0.113 - µM - 3 MT-4 HIV-1(HXB2 (PR-M46I,I47V,I50V))¶ 1.115 - µM - 3 CEM-CCRF(15% FCS) HIV-1(IIIB) 0.012;EC90=0.079 - µM - 5 CEM-CCRF(45% HUMAN PLASMA + 1.2 MG/ML a1-ACID GLYCOPROTEIN) HIV-1(IIIB) 0.039;EC90=0.146 - µM - 5

References

1. NAVIA, M.A.; SATO, V.L.; TUNG, R.D., DESIGN OF VX-478, A POTENT INHIBITOR OF HIV PROTEASE. INT ANTIVIRAL NEWS 3(9):143-145 (1995).
2. ST.CLAIR, M.H.; MILLARD J.; ROONEY J.; TISDALE M.; PARRY N.; SADLER B.M.; BLUM M.R.; PAINTER G., IN VITRO ANTIVIRAL ACTIVITY OF 141W94 (VX-478) IN COMBINATION WITH OTHER ANTIRETROVIRAL AGENTS. ANTIVIRAL RES 29:53-56 (1996).
3. PARTALEDIS, J.A.; YAMAGUCHI, K; TISDALE M.; BLAIR E.E.; FALCIONE C.; MASCHERA B.; MYERS, R.E.; PAZHANISAMY. S.; FUTER, O.; CULLINAN, A.B.; STUVER, C.M.; BYRN, R.A.; LIVINGSTON, D.J., IN VITRO SELECTION AND CHARACTERIZATION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1) ISOLATES WITH REDUCED SENSITIVITY TO HYDROXYETHYL SULFONAMIDE INHIBITORS OF HIV-1 ASPARTYL PROTEASE. J VIROL 69(9):5228-5235 (1995).
4. KIM, E.E.; BAKER, C.T.; DWYER, M.D.; MURCKO, M.A.; RAO, B.G.; TUNG, R.D.; NAVIA, M.A.; CRYSTAL STRUCTURE OF HIV-1 PROTEASE IN COMPLEX WITH VX-478, A POTENT AND ORALLY BIOAVAILABLE INHIBITOR OF THE ENZYME. J AMER CHEM SOC 117(3):1181-1182(1995).
5. LIVINGSTON, D.J.; PAZHANISAMY, S.; PORTER, D.J.T.; PARTALEDIS, J.A.; TUNG, R.D.; PAINTER, G.R., WEAK BINDING OF VX-478 TO HUMAN PLASMA PROTEINS AND IMPLICATIONS FOR ANTI-HUMAN IMMUNODEFICIENCY VIRUS THERAPY. J INFECT DIS 172(11):1238-1245(1999).
6. BABA, M.; OKAMOTO, M.; MAKINO, M.; KIMURA, Y.; IKEUCHI, T.; SAKAGUCHI, T.; OKAMOTO, T., POTENT AND SELECTIVE INHIBITION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 TRANSCRIPTION BY PIPERAZINYLOXOQUINOLINE DERIVATIVES. ANTIMICROB AGENTS CHEMOTHER 41(6):1250-1255(1997).
7. PISCITELLI, S.; VOGEL, S.; SADLER, B.; FISKE, W.; METCALF, J.; MASUR, H.; FALLOON, J., EFFECT OF EFAVIRENZ (DMP 266) ON THE PHARMACOKINETICS OF 141W94 IN HIV-INFECTED PATIENTS (ABSTRACT 346). 5TH CONF RETROVIR OPPOR INFECT 5:144(1998).
8. PAINTER, G.R.; ST CLAIR, M.H.; DEMIRANDA, P.; REYNOLDS, D.; CHING, S.; DORNSIFE, R.; LIVINGSTON, D.J.; PAZHANISAMY, S.; TUNG, R., AN OVERVIEW OF THE PRECLINICAL DEVELOPMENT OF THE HIV PROTEASE INHIBITOR VX-478 (141W94). 2ND NATL CONF HUM RETROVIRUSES RELAT INFECT 2:167(1995).

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