Identification of a 3-aminoimidazo[1,2-a]pyridine inhibitor of HIV-1 reverse transcriptase (original) (raw)
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Journal of Medicinal Chemistry, 2008
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.
Novel HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent review (2005 – 2010)
Expert Opinion on Therapeutic Patents, 2011
Highly active antiretroviral therapy (HAART) is one of the most effective means for fighting against HIV infec tion. HAART primarily targets HIV 1 reverse transcriptase (RT), and 14 of 28 compounds approved by the FDA as anti HIV drugs act on this enzyme. HIV 1 non nucleoside reverse transcriptase inhibitors (NNRTIs) hold a special place among HIV RT inhibitors owing to their high specificity and unique mode of action. Nonetheless, these drugs show a tendency to decrease their efficacy due to high HIV 1 variability and formation of resistant virus strains tolerant to clinically applied HIV NNRTIs. A combinatorial approach based on varying substituents within various fragments of the parent molecule that results in development of highly potent compounds is one of the approaches aimed at designing novel HIV NNRTIs. Generation of HIV NNRTIs based on pyrimidine derivatives explicitly exemplifies this approach, which is discussed in this review.
Journal of Medicinal Chemistry, 2007
In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors that are effective against the wild type (WT) virus and clinically observed mutants, 1,2bis-substituted benzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole led to the development of 1-(2,6-difluorobenzyl)-2-(2,6difluorophenyl)-4-methylbenzimidazole (1) (IC 50 = 0.2 μM, EC 50 = 0.44 μM, and TC 50 ≥ 100 against WT). This paper describes how substitution on the benzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhanced potency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A 7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT provided the basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivatives were nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants.
In the present study, we have designed 50 novel 1-phenyl-2, 3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid analogs as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Docking studies of the designed analogs were performed by molecular modeling software autodock 4.2 using HIV-1 reverse transcriptase (PDB ID: 1rt2) as receptor. Lipinski rule of five parameters and toxicity parameters was derived through online servers like molinspiration and Osiris property explorer. Docking parameters such as binding free energy and predicted inhibitory constant (K i ) values of the designed analogs were compared with standard drug efavirenz and co-crystallized ligand TNK-651. Among the designed analogs, TBB-II-5, TBB-II-7, TBB-II-21, TBB-II-22, TBB-II-24, TBB-II-25, TBB-II-26, TBB-II-33, TBB-II-37, TBB-II-38, and TBB-II-43 showed significant and comparable binding-free energy and predicted inhibitory constant values as that of standard drug efavirenz and TNK-651. These results indicate that, the designed analogs adopt a similar orientation and share the same binding mode as that of some of the classical non-nucleoside reverse transcriptase inhibitors within the active site of non-nucleoside inhibitory binding pocket of HIV-1 reverse transcriptase.
Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase
Bioorganic & Medicinal Chemistry Letters, 2008
A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTIresistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.
Imidazo[1,2-a]pyridin-3-amines as potential HIV-1 non-nucleoside reverse transcriptase inhibitors
Bioorganic & Medicinal Chemistry, 2011
During random screening of a small in-house library of compounds, certain substituted imidazo[1,2a]pyridines were found to be weak allosteric inhibitors of HIV-1 reverse transcriptase (RT). A library of these compounds was prepared using the Groebke reaction and a subset of compounds prepared from 2-chlorobenzaldehyde, cyclohexyl isocyanide and a 6-substituted 2-aminopyridine showed good inhibitory activity in enzymatic (RT) and HIV anti-infectivity MAGI whole cell assays. The compound showing the best anti-HIV-1 IIIB whole cell activity (MAGI IC 50 = 0.18 lM, IC 90 = 1.06 lM), along with a good selectivity index (>800), was 2-(2-chlorophenyl)-3-(cyclohexylamino)imidazo[1,2-a]pyridine-5-carbonitrile 38.
N1-Heterocyclic pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase
Bioorganic & Medicinal Chemistry Letters, 2010
A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.
Journal of Medicinal Chemistry, 2005
In the treatment of AIDS, the efficacy of all drugs, including non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the rapid appearance of drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu are some of the most common RT mutations that cause resistance to NNRTIs in the clinic. We report X-ray crystal structures for RT complexed with three different pyridinone derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 Å resolution, respectively. All three ligands exhibit nanomolar or subnanomolar inhibitory activity against wild-type RT, but varying activities against drugresistant mutants. R165481 and R221239 differ from most NNRTIs in that binding does not involve significant contacts with Tyr181. These compounds strongly inhibit wild-type HIV-1 RT and drug-resistant variants, including Tyr181Cys and Lys103Asn RT. These properties result in part from an iodine atom on the pyridinone ring of both inhibitors that interacts with the main-chain carbonyl oxygen of Tyr188. An acrylonitrile substituent on R165481 substantially improves the activity of the compound against wild-type RT (and several mutants) and provides a way to generate novel inhibitors that could interact with conserved elements of HIV-1 RT at the polymerase catalytic site. In R221239, there is a flexible linker to a furan ring that permits interactions with Val106, Phe227, and Pro236. These contacts appear to enhance the inhibitory activity of R221239 against the HIV-1 strains that carry the Val106Ala, Tyr188Leu, and Phe227Cys mutations.
Design of Annulated Pyrazoles as Inhibitors of HIV-1 Reverse Transcriptase
Journal of Medicinal Chemistry, 2008
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 13 and 14 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.