16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

R1206, A REPRESENTATIVE OF A NEW CLASS OF POTENT DIPHENYLETHER NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS BROADLY ACTIVE AGAINST NNRTI RESISTANT HIV-1 VARIANTS AND ACHIEVING HIGH SYSTEMIC EXPOSURES AND BENIGN SAFETY PROFILES IN ANIMAL SPECIES

Antivir Ther. 2007; 12:S30 (abstract no. 28)

K Klumpp, J Dunn, G Heilek, A Zhou, D Stefanidis, C-W Chen, JB Xu, J Hang, M Martin, J Davidson, S Harris, T Mirzadegan, A Paul, Y Li, G Su, T Silva, D Hirschfeld, X Han, S Swallow, N Cammack, H Vora, H Hogg and Z Sweeney
Roche Palo Alto LLC, Palo Alto, CA, USA

BACKGROUND: A series of diphenylethers was optimized to provide novel, highly potent NNRTIs with broad antiviral activity also against HIV-1 variants resistant to inhibition by currently marketed NNRTIs. Prodrugs of the antiviral parent molecules were developed to substantially increase oral bioavailability and effectively boost systemic exposures of the novel NNRTIs.

METHODS: Optimization and characterization of the diphenylether series of NNRTIs were based on structural and biochemical assessments of their binding to HIV-RT, inhibition of HIV-RT activity and inhibition of HIV replication in single and multiple-cycle replication assays in cell culture. Pharmacokinetics were determined in rats, dogs and cynomolgus monkeys and preclinical safety assessments were conducted in rats and dogs. Plasma exposures of the prodrugs, parents, and major metabolites were determined by LC-MS/MS.

RESULTS: R1206 is a representative compound of a novel series of NNRTI prodrugs. R1206 substantially increases the oral bioavailability of the antiviral compound RO-0335 in rats, dogs and monkeys. Similar to a number of other compounds in this series, RO-0335 is a potent inhibitor of wild-type HIV-1 in cell culture (mean IC₅₀=1.2 nM) and broadly active against HIV-1 strains carrying prevalent point mutations associated with resistance to current NNRTIs (K103N/Y181C, L100I/K103N, G190A, V106A, antiviral IC₅₀ fold shifts ≤1.0). RO-0335 inhibited 92% of HIV-1 viruses in a panel of 50 viruses derived from NNRTI pretreated patients with IC₅₀ values lower than 10 nM, as compared to 0% and 62% of viruses inhibited by comparator compounds Efavirenz and TMC-125, respectively. R1206 provided high oral bioavailability (33–100%) and low clearance (3–6 ml/min/kg) of RO-0335 in rats, dogs and monkeys. In safety pharmacology and subchronic toxicity studies in rats and dogs, R1206 was not associated with any significant pathological or clinical findings, while reaching plasma exposures up to 12 µM in rats and 78 µM in dogs.

CONCLUSIONS: R1206 represents a series of prodrugs for novel NNRTIs with high antiviral potency against wild-type and NNRTI-resistant HIV-1. R1206 is efficiently converted to the active parent RO-0335, achieving high oral bioavailability, high plasma exposures and benign safety pharmacology and toxicity profiles in acute and subchronic studies in rats and dogs.

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2007-06-12
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