4-Benzyl- and 4-Benzoyl-3-dimethylaminopyridin-2(1H)-ones, a New Family of Potent Anti-HIV Agents:  Optimization and in Vitro Evaluation against Clinically Important HIV Mutant Strains

Abstract

The 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 13 and 14 are representatives of a new class of highly potent non nucleoside type inhibitors of HIV-1 reverse transcriptase. To conduct SAR studies on these two lead compounds, 102 new analogues were prepared. Thirty-three compounds displayed nanomolar range activity in vitro against wild-type HIV-1, and among these, 18 were active against the 103N, Y181C, and Y188L mutant strains with IC50 values inferior to 1 microM. Evaluation of this group of analogues against an additional eight single [100I, 101E, 106A, 138K, 179E, 190A, 190S, 227C] and four double HIV mutant strains [100I + 103N, 101E + 103N, 103N + 181C, and 227L + 106A], which are often present in HIV infected patients, permitted the selection of eight compounds, 17x, 18b, 18c, 18f, 18g, 27, 30, and 42, which are globally more active than the lead molecules 13/14, emivirine and the currently used NNRTI, nevirapine. Further comparison of the 3'-CN-substituted benzoylpyridinone compound 18c, and the corresponding 3'-acrylonitrile-substituted analogue 30, to efavirenz, the reference molecule in anti-HIV therapy today, revealed that the pyridinone analogues displayed a superior inhibition profile in the in vitro cellular assay system. These results form a solid basis for continued optimization of the pyridinone series.

TMC278 (Rilpivirine): A Next‐Generation NNRTI in Phase III Clinical Development for Treatment‐Naive Patients

“…Differences of potency between the E form (TMC278) and the Z form (compound 1) were in agreement with the docking studies, which showed stronger interactions of the cyano group in the E-orientation than in the Z-orientation with the W229 region in the binding site of the RT enzyme. Except for compound 3, substituents in the alpha or beta position on the cyanovinyl group [10,12,13] did not modify the potency against the wild-type single-and double-mutant strains. The introduction of a methylene group between the vinyl and the cyano group was detrimental to the activity.…”

“…The marked structural diversity that is displayed by these classes of compounds would suggest that there are still ample opportunities to discover new highly potent NNRTIs. Johnson & Johnson pharmaceutical research and development, in partnership with Institut-Curie (France), contributed to the discovery of the arylpyridone class, with 4-benzyl-3-dimethylamino-2-pyridone (R131459) as the first representative compound [12]. This compound, a hybrid of the Merck pyridone L-697,661 and HEPT derivative, is active at submicromolar concentrations against wild-type HIV-1 and maintains a good level of activity against NVPresistant HIV-1 strains.…”

Pyridin‐2(1H)‐ones: A Promising Class of HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors

“…[19] Pyridinone-HEPT hybrids Considering the partial structure similarity of Merck pyridinones and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) derivatives such as GCA-186 (Figure 2), a very extensive synthetic program was initiated leading to the development of a series of potent pyridinone-HEPT hybrids. Subtypes of these hybrids include 4-arylthiopyridin-2(1H)-ones, [20,21] 4-benzylpyridin-2(1H)-ones, [22][23][24] 4-aryloxypyridin-2(1H)-ones, [25,26] and 4-benzoylpyridin-2(1H)-ones. [23,24] 4-Benzylpyridin-2(1H)-ones were further coupled with the nucleoside RT inhibitor azidothymidine (AZT) to test a hypothesis of "mixture site" inhibitors.…”

“…Subtypes of these hybrids include 4-arylthiopyridin-2(1H)-ones, [20,21] 4-benzylpyridin-2(1H)-ones, [22][23][24] 4-aryloxypyridin-2(1H)-ones, [25,26] and 4-benzoylpyridin-2(1H)-ones. [23,24] 4-Benzylpyridin-2(1H)-ones were further coupled with the nucleoside RT inhibitor azidothymidine (AZT) to test a hypothesis of "mixture site" inhibitors. However, the pyridinone-AZT conjugates were inactive.…”

“…[26] A very attractive feature of the pyridinone-HEPT hybrids is that recently developed 4-benzoylpyridin-2(1H)-ones such as 11, 12, and 13 show activity against a large panel of clinically relevant HIV-1 mutant strains and seem to display a more attractive inhibitory profile than efavirenz. [23,24] Furthermore, the 4-aryloxypyridin-2(1H)-ones R165481 (14) and R221239 (15) show activity against mutant strains K103N and Y181C and the double mutant K103N + Y181C at nanomolar concentrations. [26] Binding Mode into the NNRTIs Binding Pocket Automated docking and 3D-QSAR of Merck pyridinones As mentioned earlier, biological experiments showed that A C H T U N G T R E N N U N G L-697,661, L-697,639, L-696,229, and other related Merck pyridinones should bind in the NNRTIs pocket.…”