Novel HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent review (2005 - 2010)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) form the backbone of antiretroviral treatment for many HIV-infected individuals. The unique antiviral activity, high specificity and low toxicity associated with this class of agents make them a frequent choice for first-line therapy. However, the effectiveness of NNRTI drugs can be hampered by the rapid emergence of drug-resistant viruses, poor pharmacokinetic (PK) properties and severe side effects in long-term usage. Therefore, there is an urgent need to develop novel NNRTIs without such limitations. An analysis of this vast group of already existing inhibitors should constitute the basis of the effort toward the development of more potent, promising drugs or candidates.

The present review provides an overview of NNRTI research from 2005 to 2010, and highlights some important medicinal chemistry principles and strategies in the development of NNRTIs.

An in-depth analysis of the common binding configuration and structural features of NNRTIs, as well as the underlying clues to the 'follow-on'-based chemical evolution efforts (including the key medicinal chemistry principles and strategies: bioisosteric replacement, molecular hybridization, scaffold hopping, prodrug, etc.) has greatly accelerated the optimization of the pharmacodynamic (PD) and PK profiles. There is still a good deal of opportunity to discover new highly potent NNRTIs or novel scaffolds with unconventional mechanisms for reverse transcriptase (RT) inhibition.