2007
DOI: 10.1016/j.bmcl.2006.11.063
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Respiratory syncytial virus fusion inhibitors. Part 4: Optimization for oral bioavailability

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Cited by 63 publications
(57 citation statements)
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“…66 To address this metabolic liability of 43, these investigators replaced the dimethylamino ethyl substituent at N 1 of the benzimidazole ring with the butyronitrile moiety and the bulky substituent at benzimidazolone ring with a small substituent (e.g., isopropyl) to yield compound 44, having 19 excellent antiviral potency and Caco-2 permeability as shown in Figure 19. 14 Figure 19. Compound 45 showed excellent plasma exposure in rats, mice, dogs and monkeys, a dose-dependent reduction in RSV titers in the lungs of infected animal models, and did not produce genotoxicity in the Ames mutation assay, and an IC 50s >26.5 µM against major drug metabolizing CYP450 isoforms.…”
Section: Compound 38 (Simeprevir/olysio): Compound 38 (Tmc435/simeprementioning
confidence: 97%
See 1 more Smart Citation
“…66 To address this metabolic liability of 43, these investigators replaced the dimethylamino ethyl substituent at N 1 of the benzimidazole ring with the butyronitrile moiety and the bulky substituent at benzimidazolone ring with a small substituent (e.g., isopropyl) to yield compound 44, having 19 excellent antiviral potency and Caco-2 permeability as shown in Figure 19. 14 Figure 19. Compound 45 showed excellent plasma exposure in rats, mice, dogs and monkeys, a dose-dependent reduction in RSV titers in the lungs of infected animal models, and did not produce genotoxicity in the Ames mutation assay, and an IC 50s >26.5 µM against major drug metabolizing CYP450 isoforms.…”
Section: Compound 38 (Simeprevir/olysio): Compound 38 (Tmc435/simeprementioning
confidence: 97%
“…The lipophilicity of a compound can be reduced by replacing the isopropyl (clogP ~ 1.5) and phenyl (clogP ~ 2.0) groups with the less lipophilic and isosteric cyclopropyl (clogP ~ 1.2) group. [14][15][16] Similarly, increased metabolic stability is achievable through a) replacing the N-ethyl group, which is susceptible to CYP450-mediated oxidation, with the metabolically stable N-cyclopropyl moiety; 17,18 b) the spirocyclopropanation at the α-C of the glycine amide bond to prevent amide hydrolysis 19 and c) the replacement of the metabolically labile benzylic carbon atom with the spirocyclopropane. 20 Furthermore, locking the E/Z-isomerizable non-cyclic alkene bond into a cyclopropane ring can lead to geometrically stable isomers for in vivo studies.…”
Section: Influence Of the Cyclopropane Ring On Pharmacological Activitymentioning
confidence: 98%
“…19,20 BMS-433771 (5) is an orally bioavailable and modestly potent RSV inhibitor showing an EC 50 of 24 nM over a range of both laboratory and clinically relevant RSV strains. 21 BMS-433771 was progressed into preclinical evaluation. 22 Although the above advantages endorsed BMS-433771 for preclinical development, some potential concerns caught our attention according to our internal assessment, including modest activity, high in vivo clearance, short T 1/2 duration time (36 min), etc.…”
mentioning
confidence: 99%
“…Benzimidazol‐2‐ones have various biological functions. For example, they are used as inhibitors of respiratory syncytial virus (RSV) fusion,13 non‐nucleoside reverse transcriptase (NNRT),14 and farnesyltransferase (FTase)15 as well as antagonists of the progesterone receptor 16. Correspondingly, methods for the synthesis of these compounds have been developed.…”
Section: Introductionmentioning
confidence: 99%