Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate. 2. Discovery of a Morpholinopropylaminobenzimidazole Derivative (TMC353121)

Bonfanti, Jean‐François; Meyer, Christophe; Doublet, Frédéric; Fortin, Jérôme; Müller, Philippe; Quéguiner, Laurence; Gevers, Tom; Janssens, Peggy; Szel, Heidi; Willebrords, R.; Timmerman, Philip; Wuyts, Koen; Remoortere, P. Van; Janssens, Frans; Wigerinck, Piet; Andries, Koen

doi:10.1021/jm701284j

Cited by 88 publications

(65 citation statements)

References 13 publications

(59 reference statements)

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“…It maintains high activity (pEC50 9.9) and low cytotoxicity, while presenting a shorter retention time in the lung (lung t 1/2 25 h) [19]. The mechanism of action of TMC353121 has been confirmed in time-ofaddition and in vitro resistant mutant selection studies.…”

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confidence: 85%

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Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

Olszewska¹,

Ispas²,

Schnoeller³

et al. 2010

European Respiratory Journal

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Respiratory syncytial virus (RSV) causes bronchiolitis in young children and common colds in adults. There is no licensed vaccine, and prophylactic treatment with palivizumab is very expensive and limited to high-risk infants. Ribavirin is used as an antiviral treatment in infants and immunosuppressed patients, and its use is limited due to side-effects, toxicity to the recipient and staff, and evidence of marginal clinical efficacy. Therefore, we studied the in vivo kinetics, and the antiviral and protective properties of a novel candidate for RSV disease treatment.The drug is a small molecule (TMC353121) discovered by screening for fusion inhibitory properties against RSV in a cellular infection model. The pharmacokinetics of TMC353121 was studied in BALB/c mice and antiviral effects determined by testing viral loads in lung tissue by quantitative RT-PCR and plaque assay after intranasal RSV infection.At doses of 0.25-10 mg?kg -1 , TMC353121 significantly reduced viral load, bronchoalveolar lavage cell accumulation and the severity of lung histopathological change after infection. Treatment remained effective if started within 48 h of infection, but was ineffective thereafter. Therefore, TMC353121 is a novel potent antiviral drug, in vivo reducing RSV replication and inhibiting consequential lung inflammation, with a great potential for further clinical development.

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confidence: 85%

“…TMC353121 [19,21] was administered intravenously in saline at doses of 0.25-10 mg?kg -1 , and at various times in relation to the RSV infection ( fig. 1a).…”

Section: Animals and Drug Administrationmentioning

confidence: 99%

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

Olszewska¹,

Ispas²,

Schnoeller³

et al. 2010

European Respiratory Journal

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“…Several direct-acting, small-molecule inhibitors targeting different steps of the RSV life cycle were tested, including TMC-353121, an entry inhibitor targeting the RSV fusion protein (13); RSV-604, an early postentry inhibitor binding a conserved region of the nucleocapsid protein (14,15); YM-53403, an inhibitor targeting the RSV polymerase in variable region 2 (16); and BI-D, an inhibitor targeting the RSV polymerase in domain V (17). The mechanisms of inhibition by RSV-604 and YM-53403…”

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confidence: 99%

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

McCutcheon

Jordan

Mawhorter

et al. 2016

J Virol

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Human respiratory syncytial virus (RSV) is a single-stranded RNA virus that causes acute, and occasionally fatal, lower respiratory illness in young infants, the elderly, and immunocompromised patients. Therapeutic interventions able to cut short viral replication and quickly return the airways to normal function are needed. An understanding of antiviral activities and their effects on host defense mechanisms is important for the design of safe and effective therapy. We targeted functionally and temporally distinct steps within the viral life cycle using small-molecule RSV inhibitors and studied their antiviral activities and their effects on innate interferon responses of airway epithelial cells in vitro. H uman respiratory syncytial virus (RSV) is a single-stranded, negative-sense RNA virus belonging to the family Paramyxoviridae. Premature and very young infants are at the highest risk of having severe lower respiratory tract infections and, later, a higher incidence of chronic asthma (1). Older adults with chronic lung or heart disease and individuals with suppressed immune systems also often require medical care after RSV infection. The lack of long-lasting protection after primary infection contributes to the capacity of RSV to cause yearly outbreaks and has challenged vaccine development (2). Synagis, a monoclonal antibody (MAb) directed against the RSV fusion protein, has shown prophylactic utility, but its cost and intramuscular route of administration have limited its use to hospitalized, high-risk infants Ͻ2 years of age (2). The only therapeutic intervention for RSV infection currently available to patients is the use of ribavirin (3), but its use is also limited because of poor efficacy and teratogenicity and the requirement of an aerosol and/or intravenous (i.v.) mode of administration in hospital settings (4). New therapeutic interventions able to lower the viral load, decrease transmission, and prevent lower respiratory complications are needed.RSV infection is initiated by attachment of the viral G protein to the surface of airway epithelial (AE) cells (5,6). Following attachment, the viral F protein mediates fusion of the viral and cellular membranes, allowing the RSV ribonucleic protein (RNP) complex, comprised of the viral RNA genome encapsulated with nucleoprotein (N) and associated with the phosphoprotein (P) and RNA-dependent RNA polymerase (L), to enter the cytoplasm. The RNP complex performs viral transcription to produce capped and polyadenylated mRNAs and genome replication. Detailed understanding of RSV biology is made difficult by the intimate coupling of transcription and replication activities. Furthermore, the RSV polymerase is large and complex, containing multiple domains and enzymatic activities that allow it to function and be

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“…This great attention is essentially due to their wide range of biopharmacological activities including antihelminthic [1], antitumoral [2], antimicrobial [3], antifungal [4], antiviral [5], antihistaminic and antiallergic [6] properties. The benzimidazole derivatives showed to be also excellent inhibitors of HIV-1 reverse transcriptase [7].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of 1-(1H-benzimidazol-2-yl)-3- (3-nitrophenyl)prop-2-en-1-one, C16H11N3O3

Bisseyou¹,

Guillot²,

Sissouma³

et al. 2011

Zeitschrift Für Kristallographie - New Crystal Structures

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C 16 H 11 N 3 O 3 ,monoclinic, P12 1 /c1(no. 14), a =9.3959(2) Å, b =5.7085(1) Å, c =24.8921(7) Å, b =96.885(1)°, V =1325.5 Å 3 , Z =4,Rgt(F) =0.041, wRref(F 2 ) =0.152, T =100 K.Source of material 2-Acetylbenzimidazole (1.5 g, 10 mmol) was dissolved to asolution of EtOH (40 ml) and 3g(75 mmol) of NaOH. To this solution, 10 mmol of 3-nitrobenzaldehyde was added. The mixture was stirred at ambient temperature during 5h.The resulting mixture was neutralized with a4Nsolution of HCl. The precipitate was dried and recrystallized from amixture of toluene/EtOH (4 : 1, v/v)(yield 68 %, m.p. >533 K). Yellow crystals of parallelepiped shape suitable for single-crystal diffraction were grown by slow evaporation at ambient temperature and in air from ahot solution in acetonitrile. NMR data are available in the CIF. Experimental details DiscussionBenzimidazole and its derivatives constitute one of the most extensively studied families of organic compounds in regard to the number of articles published on these compounds. This great attention is essentially due to their wide range of biopharmacological activities including antihelminthic [6] properties. The benzimidazole derivatives showed to be also excellent inhibitors of HIV-1 reverse transcriptase [7]. The benzimidazole nucleus system, whose inestimable virtues seduced the scientific community, was moreover classified as an important pharmacophore in the discovery of modern drug [8]. From this point of view, the benzimidazole nucleus system constitutes abasic molecular scaffold in the design of new molecules of pharmacological interest. The title molecular structure consists of three main parts: the benzimidazole ring and the nitrophenyl ring related by enone group (figure, top). In the benzimidazole ring the bond lengths and angles are in good agreement with those observed in the 1-(1H-benzimidazol-2-yl)-3-(3-chlorophenyl)-prop-2-en-1-one [9]. The C10=N2 double bond and C16-N2 single bond in the imidazole ring are clearly distinguishable with bond lengths of 1.323(2) and 1.387(1) Å,r espectively. The benzimidazole ring makes dihedral angles of 2.66(3)°and 1.16(3)°with phenyl ring and mean plane of enone group, respectively. It confers to the molecule an almost planar structure. The magnitudes of structural parameters of phenyl ring are within normal ranges [10], with a light opening of intramolecular angle at C4 atom due to the presence of nitro group which is twisted of 13°with respect of phenyl ring. The N3-O2 and N3-O3 bonds of nitro group have similar distances of 1.226 (2)

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Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate. 2. Discovery of a Morpholinopropylaminobenzimidazole Derivative (TMC353121)

Cited by 88 publications

References 13 publications

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

Crystal structure of 1-(1H-benzimidazol-2-yl)-3- (3-nitrophenyl)prop-2-en-1-one, C16H11N3O3

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