Diphenyl ether non-nucleoside reverse transcriptase inhibitors with excellent potency against resistant mutant viruses and promising pharmacokinetic properties.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are part of the preferred treatment regimens for individuals infected with HIV. These NNRTI-based regimens are efficacious, but the most popular NNRTIs have a low genetic barrier to resistance and have been associated with adverse events. There is therefore still a need for efficacious antiviral medicines that facilitate patient adherence and allow durable suppression of viral replication. As part of an extensive program targeted toward the discovery of NNRTIs that have favorable pharmacokinetic properties, good potency against NNRTI-resistant viruses, and a high genetic barrier to drug resistance, we focused on the optimization of a series of diaryl ether NNRTIs. In the course of this effort, we employed molecular modeling to design a new set of NNRTIs that that are active against wild-type HIV and key NNRTI-resistant mutant viruses. The structure-activity relationships observed in this series of compounds provide insight into the structural features required for NNRTIs that inhibit the replication of a wide range of mutant viruses. Selected compounds have promising pharmacokinetic profiles.

Design of annulated pyrazoles as inhibitors of HIV-1 reverse transcriptase.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class.The binding mode maintains the beta13 and beta14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture.

Enantioselective synthesis of medium-ring heterocycles, tertiary ethers, and tertiary alcohols by Mo-catalyzed ring-closing metathesis.

The Mo-catalyzed asymmetric ring-closing metathesis (ARCM) of various achiral trienes leads to the formation of medium-ring unsaturated heterocycles in high yield and with excellent enantioselectivity. Reactions may be carried out on gram scale and in the absence of solvent. The unsaturated siloxanes obtained enantioselectively can be readily functionalized to obtain synthetically useful and difficult-to-access tertiary alcohols.

An enantiomerically pure adamantylimido molybdenum alkylidene complex. An effective new catalyst for enantioselective olefin metathesis.

An enantiomerically pure Mo-based complex that bears an alkylimido ligand is prepared and characterized through NMR spectroscopy and X-ray analysis. Mo complex 4 is the only reported chiral alkylimido catalyst; all previous chiral complexes are arylimido systems. These studies show that the chiral Mo catalyst exists exclusively as the syn isomer and that it offers unique reactivity and selectivity profiles in asymmetric olefin metathesis.