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Fifth International CongressDrug Therapy in HIV Infection22-26 October, 2000
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R165335–TMC125, a novel non nucleoside reverse transcriptase inhibitor (NNRTI) with nanomolar activity against NNRTI resistant HIV strains
K. Andries1, M.-P. de Béthune2, D.W. Ludovici3, M.J. Kukla3, H. Azijn2, P. Lewi4, P.A.J. Janssen4 and R. Pauwels2
1 Janssen Research Foundation, Beerse, Belgium; 2 Tibotec, Mechelen, Belgium; 3 Janssen Research Foundation, Spring House, Pennsylvania, USA; 4 Janssen Research Foundation, Vosselaar, Belgium
Int Cong Drug Therapy HIV 2000 Oct 22-26;5:Abstract No. PL4.5
AIDS 2000, Oct 22-26;14(Suppl. 4); S4-S5
NNRTIs are very potent anti-HIV drugs with good activity in combination therapy, including protease inhibitors sparing regimens. However extensive cross-resistance is observed for the current inhibitors of this class. In order to be useful, new NNRTIs need to be active on such resistant viruses. To rapidly identify new compounds active on NNRTI resistant strains, we applied a parallel, instead of a sequential screening strategy, in which candidates were simultaneously tested on wild type (wt) and a subset of resistant HIV mutants with clinically relevant mutations. Serum protein binding and metabolic stability were addressed very early in the selection process. The selection criteria were: IC50 ≤ 100 nM/l against wt HIV, IC50 ≤ 100 nM/l against NNRTI resistant strains, low serum protein binding (IC50 increase ≤ 5) and high in vitro metabolic stability (IC50 decrease < 20% upon 2 h incubation in human liver microsomes).
Evaluation of > 300 triazine and pyrimidine analogues of a lead molecule led to the identification of a series of compounds active in the nanomolar range against both wt and resistant strains. R165335–TMC125, a diaminopyrimidine (DAPY) derivative, had the best antiviral potency profile. In addition, the compound is not toxic in MT4 cells (CC50 > 100μM), is stable in human liver microsomes (< 20% degradation) and its IC50 does not increase significantly in the presence of human serum albumin or &alpha1acid glycoprotein (± 5 or 2-fold respectively).
| HIV Strain | IC50 (nM) Nevirapine | Delavirdine | Efavirenz | R165335–TMC125 | |
| LAI (wt) | 450 | 16 | 1.0 | 1.4 | |
| L1 001 | 2360 | 3467 | 38 | 3 | |
| K103N | < 100 000 | 1697 | 39 | 1.3 | |
| Y181C | < 100 000 | 1336 | 2 | 7 | |
| Y188L | < 100 000 | 187 | 144 | 4 | |
| K103N+L100I | < 100 000 | < 10 000 | < 10 000 | 19 | |
| K103N+Y181C | < 100 000 | < 10 000 | 43 | 4 |
Presenting author: K. Andries
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2000-10-22
PL4-5
Originally published in AIDS Volume 14, Supplement 4 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701
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