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Dihydroxy-pyrimidine and N-methylpyrimidone HIV-integrase inhibitors: Improving cell based activity by the quaternarization of a chiral center |
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| Authors: | Emanuela Nizi Maria Vittoria Orsale Benedetta Crescenzi Giovanna Pescatore Ester Muraglia Anna Alfieri Cristina Gardelli Stéphane AH Spieser Vincenzo Summa |
| Institution: | 1. Department of Medicinal Chemistry, IRBM-Merck Research Laboratories Rome, Via Pontina Km 30,600, 00040 Pomezia, Italy;2. Department of Drug Metabolism, IRBM-Merck Research Laboratories Rome, Via Pontina Km 30,600, 00040 Pomezia, Italy |
| Abstract: | In the context of HIV-integrase, dihydroxypyrimidine and N-methyl pyrimidone inhibitors the cellular activity of this class of compounds has been optimized by the introduction of a simple methyl substituent in the α-position of the C-2 side chains. Enhanced passive membrane permeability has been identified as the key factor driving the observed cell-based activity improvement. The rat PK profile of the α-methyl derivative 26a was also improved over its des-methyl exact analog. |
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