Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors

Sun, Lian Qi; Qin, Bingjie; Huang, Li; Qian, Keduo; Chen, Chin Ho; Lee, Kuo Hsiung̀; Xie, Linghai

doi:10.1016/j.bmcl.2012.02.055

Cited by 16 publications

(11 citation statements)

References 12 publications

(15 reference statements)

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“…These compounds are highly effective NNRTIs that have strong potential for development as new anti-HIV-1 drugs with improved antiviral efficacy and drug resistance profiles (Lee et al, 2013(Lee et al, , 2014Frey et al, 2014Frey et al, , 2015Gray et al, 2015). As noted in Table 1, these compounds are suitable drug candidates for further preclinical studies due to their low effective intrinsic inhibitory activities at low nanomolar concentrations, better solubility profiles, and low C log P values compared with rilpivirine (Janssen et al, 2005;Sun et al, 2012) and efavirenz (Lee et al, 2013(Lee et al, , 2014Frey et al, 2014). Our in vitro pharmacological profiling of these compounds against a broad range of targets, which are associated with off-target effects in humans, has shown that these compounds exhibit little to no adverse effects on these targets (Fig.…”

Section: Discussionmentioning

confidence: 99%

Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

et al. 2017

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The clinical benefits of HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are hindered by their unsatisfactory pharmacokinetic (PK) properties along with the rapid development of drug-resistant variants. However, the clinical efficacy of these inhibitors can be improved by developing compounds with enhanced pharmacological profiles and heightened antiviral activity. We used computational and structure-guided design to develop two next-generation NNRTI drug candidates, compounds I and II, which are members of a class of catechol diethers. We evaluated the preclinical potential of these compounds in BALB/c mice because of their high solubility (510 mg/ml for compound I and 82.9 mg/ml for compound II), low cytotoxicity, and enhanced antiviral activity against wild-type (WT) HIV-1 RT and resistant variants. Additionally, crystal structures of compounds I and II with WT RT suggested an optimal binding to the NNRTI binding pocket favoring the high anti-viral potency. A single intraperitoneal dose of compounds I and II exhibited a prolonged serum residence time of 48 hours and concentration maximum (C max ) of 4000-to 15,000-fold higher than their therapeutic/effective concentrations. These C max values were 4-to 15-fold lower than their cytotoxic concentrations observed in MT-2 cells. Compound II showed an enhanced area under the curve (0-last) and decreased plasma clearance over compound I and efavirenz, the standard of care NNRTI. Hence, the overall (PK) profile of compound II was excellent compared with that of compound I and efavirenz. Furthermore, both compounds were very well tolerated in BALB/c mice without any detectable acute toxicity. Taken together, these data suggest that compounds I and II possess improved anti-HIV-1 potency, remarkable in vivo safety, and prolonged in vivo circulation time, suggesting strong potential for further development as new NNRTIs for the potential treatment of HIV infection.

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Section: Discussionmentioning

confidence: 99%

Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

et al. 2017

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“…A key physiochemical property for an effective orally administered drug is aqueous solubility. The second-generation FDA-approved diarylpyrimidine (DAPY) NNRTIs etravirine and rilpivirine, with reported aqueous solubility of ≪1 [7] and 0.02–0.24 μg/ml [8,9], respectively, have poor solubility, limiting the ease of formulation and bioavailability [7]. Given the poor solubility of approved DAPY NNRTIs, our drug design efforts focused on the addition of solubilizing groups to a structurally related class of NNRTIs, the diaryltriazines (DATAs).…”

Section: Introduction1mentioning

confidence: 99%

A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase

Mislak

Frey

Bollini

et al. 2014

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are vital in treating HIV-1 infection by inhibiting reverse transcriptase (RT). Drug toxicity and resistance drive the need for effective new inhibitors with improved physiochemical properties and potent antiviral activity. Computer-aided and structure-based drug design have guided the addition of solubilizing substituents to the diaryltriazine scaffold. These derivatives have markedly improved solubility and maintain low nanomolar antiviral activity against RT. The molecular and structural basis of inhibition for this series was determined to facilitate future inhibitor development with improved pharmacological profiles. Methods The molecular mechanism of inhibition was investigated using transient-state kinetic analysis. Crystal structures of RT in complex with each inhibitor were obtained to investigate the structural basis of inhibition. Results The diaryltriazine and its morpholine derivative have RT inhibition constants of 9±2 nM and 14±4 nM, respectively. They adopt differential binding modes within the non-nucleoside inhibitor binding pocket to distort the catalytic site geometry and primer grip regions. The novel morpholinopropoxy substituent extends into the RT/solvent interface of the NNIBP. Conclusions Kinetic and structural analyses show that these inhibitors behave as conventional NNRTIs and inhibit the polymerization step. This study confirms appending solubilizing substituents on the azine ring of diaryltriazine class of NNRTIs that extend into the RT/solvent interface effectively maintains low nanomolar potency and improves physiochemical properties. General Significance The modification of NNRTI scaffolds with solubilizing substituents, which extend into the RT/solvent interface, yields potent antivirals and is an effective strategy for developing novel inhibitors with improved pharmacological properties.

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“…Our aim was to develop potential new drug candidates with both good in vitro antiviral potency and acceptable drug-like properties. Based on prior SAR results, [11,12] we know that the para -cyanophenyl moiety (A-ring), the central pyridine (B-ring) with a 3-amino group and the NH linker between these two rings are necessary pharmacophores of DAPAs as HIV-1 NNRTIs. Especially, the presence of the 3-amino group on the central pyridine ring is crucial for interaction with a key amino acid K101 on the NNRTI binding site, acting as both H-bond donor and acceptor to form multiple H-bonds.…”

Section: Introductionmentioning

confidence: 99%

Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6‐Diarylpyridinamines as a Novel Class of HIV‐1 NNRTIS

Wu¹,

Liu²,

Qin³

et al. 2014

ChemMedChem

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Nineteen new halogenated diarylpyridinamine (DAPA) analogues (6a-n and 8a-e) modified on the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50 < 10 nM). Particularly, (E)-6-(2”-bromo-4”-cyanovinyl-6“-methoxy)phenoxy-N2-(4′-cyanophenyl)pyridin-2,3-diamine (8c) displayed low nanomolar antiviral potency (3–7 nM) against wild-type and resistant viral strains with E138K or K101E mutation, associated with resistance to rilvipirine (1b). Compound 8c exhibited much lower resistance fold changes (RFC 1.1–2.1) than 1b (RFC 11.8–13.0). Compound 8c also exhibited better metabolic stability (in vitro half-life) than 1b in human liver microsomes (HLM), possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE > 0.3, LLE >5, LELP <10). With balanced potency and drug-like properties, 8c merits further development as an anti-HIV drug candidate.

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Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors

Cited by 16 publications

References 12 publications

Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase

Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6‐Diarylpyridinamines as a Novel Class of HIV‐1 NNRTIS

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