A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of the pharmacokinetic profile of substituted benzimidazoles by reducing their tissue retention. However, the modifications that were necessary to achieve this goal also led to a significant drop in anti-RSV activity. This paper describes a molecular modeling study followed by a lead optimization program that led to the recovery of the initial potent antiviral activity and the selection of TMC353121 as a clinical candidate.
We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.
The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl)thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on the endo-nitrogen atom. After deprotection of the piperidine nitrogen atom with 48% aqueous hydrobromic acid solution, the title compounds were obtained by three different methods, viz. alkylation, reductive amination, or oxirane ring-opening reactions. The in vivo antihistaminic activity was evaluated by the compound 48/80 induced lethality test in rats and histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action, for a selected number of compounds, was studied in the guinea pig. The phenylethyl derivatives showed the most potent antihistamine properties after oral administration in both animal species.
The synthesis of a series of N-1,4-disubstituted-1,4-dihydro-5H-tetrazol-5-one piperidinyl derivatives of fentanyl, carfentanil, and sufentanil is described. The 1-substituted tetrazolinones 2 were essentially prepared via the addition reaction of aluminium azide to isocyanates or acid chlorides in tetrahydrofuran. Alkylation of 2 under neutral or weakly basic conditions afforded almost exclusively the 1,4-disubstituted tetrazolinone isomer 3. N-Alkylation of the piperidine derivatives 4 with 3 in dimethylformamide yielded 9a-v. The morphinomimetic activity in rats, after intravenous injection of the compounds, was evaluated in the tail withdrawal reflex test. The fentanyl analogues 9a-c (R4 = H) are inactive at the measured dose of 2.5 or 10 mg/kg (iv). For the carfentanil analogues (R4 = COOCH3) maximal narcotic activity is found when R1 represents a lower alkyl group (9d-f) or a thienylethyl group (9n). The sufentanil analogues (R4 = CH2OCH3) show the same structure-activity relationship (SAR) profile as the carfentanil derivatives (R4 = COOCH3). The structural requirements for optimal activity are in good agreement with earlier observations in the series of 10-12. From the series the ethyl tetrazolinone derivative 9r, alfentanil (R 39209), was selected for clinical investigation. As an analgesic in rats, 9r is 140 times more potent than pethidine 15 and 72 times more potent than morphine 14. Alftentanil reaches its peak effect within 1 min after injection, and its duration of action is very short; at 2 times its MED50, 9r has a duration of action of 11 min. This duration is 30 min for 10 and 90 min for 14. Compared to 10, alfentanil 9r is about 4 times faster but 3 times shorter acting. Structurally, 9r shows most resemblance to sufentanil 12, since it differs only by substitution of a 4-ethyltetrazolinone ring for the thiophene ring. The considerable differences in their pharmacological profiles were explained in terms of marked variations in physicochemical and, hence, pharmacokinetic properties.
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