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  • The biochemical cell culture activities and properties of bi

    2021-09-18

    The biochemical, cell culture activities and properties of bicyclic carboxamides are compiled in , with the prototype of the series, 4-fluorobenzyl carboxamide , displaying an antiviral profile comparable to the spirocyclic carboxamide . The introduction of a small hydrophobic methyl () and chloride () substituents at the meta-position of the benzyl ring did not significantly affect the intrinsic antiviral activity, although the HSA-derived potency shift was exacerbated. In contrast, in the presence of HAS, the -methyl and -chloro analogs and , respectively, exhibited substantially reduced activities. In contrast to the observations made with , analogs , containing polar -substituents, exhibited potent antiviral activities and displayed lower potency shift in the presence of HSA. The morpholino analog showed potent antiviral activity that was reduced about 10-fold in the presence of HSA. The -methylcarboxamide displayed an interesting profile, expressing potent antiviral activity that was negligibly affected by HSA in spite of reduced potency in the biochemical assay. Finally, the methylsulfonyl (), the dimethylsulfamoyl () and the cyclic-sulfonamide () analogs exhibited potent antiviral activities that were subject to modest ≤4-fold shift in the EC value in the presence of HSA. Several of these compounds were evaluated in rat pharmacokinetic studies and the clearance data following IV dosing is presented in the . Compounds , and displayed low clearance whereas , , and exhibited moderate to high clearance in the rat. Compound with potent antiviral activity and low potency-shift (≤10x) in the presence of either 15 mg/mL HSA or 40% human serum (HS) was further evaluated in additional studies, the results of which are summarized in . Plasma protein binding of was high in all species (≥93.7%) and the Ivacaftor benzenesulfonate was not overtly cytotoxic to several cell lines, with CC values of ≥45 μM. The crystalline solubility of ranged from 9 to 63 μg/mL in the physiological pH range at room temperature and increased as the pH increased, all the while demonstrating satisfactory solution and solid-state stability under various conditions. Caco-2 studies revealed high permeability with no indication of efflux. In studies designed to assess the potential for drug-drug interactions, the IC values toward human CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes were >40 μM, classifying as a relatively weak CYP inhibitor, for which drug interactions involving CYP substrates were not anticipated. Minimal transactivation of human PXR (EC and EC > 50 μM) or induction of CYP3A4 mRNA (tested up to 100 μM of in Fa2N-4 immortalized human hepatocytes) was observed, and thus, significant induction of CYP3A4 was not expected. Compound was not a substrate of human P-glycoprotein (P-gp) and was a relatively weak inhibitor of this efflux pump (5% inhibition of [H]-digoxin transport at 10 μM), and, therefore, drug interactions involving P-gp were not expected. The half-life values of in a phase I metabolic oxidation assay (CYP-NADPH) were ≥96 min in human, dog, monkey and rat, data that suggest low potential for oxidation by the CYPs. Compound was not mutagenic in a bacterial reverse mutation assay ( strains TA98 and TA100) at ≤5000 μg/plate with and without metabolic activation. An cytokinesis-blocked micronucleus study was performed to determine the potential of to induce micronuclei in cultured Chinese hamster ovary (CHO) cells exposed to ≤500 μg/mL (≈1.4 mM). Compound was not clastogenic in CHO cells exposed either to ≤ 1.4 mM for 3 h in the presence of metabolic activation or to ≤ 0.36 mM for 22.5 h in the absence of metabolic activation. Compound emerged as a lead compound based on its antiviral activity and lead profiling properties and was advanced into full pharmacokinetic profiling studies in three preclinical species. The results of pharmacokinetic studies conducted in the rat, monkey, and dog, performed using PEG 400/ethanol (90:10) solutions, are summarized in . Compound was characterized as a low clearance compound in the rat, dog and monkey with moderate to long elimination half-lives in all species. The volume of distribution was low across the species, indicating that compound distribution outside of the plasma is minimal. When was dosed in solution, the oral exposure was high and absolute oral bioavailabilities ranged between 56 and 129%. The t of 0.25 h suggests rapid absorption of the compound in all 3 species. In dog cardiovascular and two week rat toxicity studies, (BMS-707035) demonstrated good safety margins data that collectively contributed to its selection as a clinical candidate