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  • Synthesis of these hydrazide inhibitors

    2021-09-10

    Synthesis of these hydrazide inhibitors is outlined in , . Condensation of Boc-carbazate with desired aldehyde resulted in hydrazone of type which were reduced to alkylated hydrazides using NaBH and toluenesulfonic acid. The resulting alkylated hydrazides were acylated with 98 synthesis chlorides or isocyanates to yield desired amides or ureas of type . These acylated derivatives were deprotected to form hydrazide salts of type that were further used for syntheses of inhibitors. Coupling of dimethylcyclopropanated proline derivative with P amino acid using HATU coupling agent resulted in dipeptides of type The Boc group of was deprotected using 4M HCl in dioxane and capped with appropriate P-capping group using corresponding isocyanate to yield compounds of type The methyl ester was hydrolyzed with aq lithium hydroxide and the resulting acid was coupled with hydrazide salt of type to obtain aza-peptide inhibitors of type . Synthesized inhibitors of type were evaluated for their ability to inhibit HCV NS3 protease in a continuous assay as previously described to obtain a . Compounds with good binding were further evaluated in a replicon based cellular assay to determine EC Based on our experience from ketoamide derived inhibitors we decided to evaluate inhibitors derived from dimethylcylclopropanated proline as P, and glutarimide derived P capping. We first evaluated various novel groups derived from amides, carbamates and ureas (). Introduction of benzamide at resulted in compound that demonstrated a =52.0μM (). Replacement of benzamide moiety with acetamide group resulted in compound with =22μM, a marginal improvement in potency compared to . However, introduction of cyclopropyl amide resulted in compound with improved binding =3.0μM and EC=15.0μM. Similarly, incorporation of a phenethyl amide at resulted in compound with much improved binding =0.72μM and EC=3.5μM. This was our first compound in this series to demonstrate a binding less than 1μM. We next explored the incorporation of carbamates and ureas at this position. Synthesis of the -butyl carbamate analog resulted in compound with =3.1μM and EC=24.0μM whereas introduction of -butyl urea resulted in compound with =1.6μM. Since the urea analogs demonstrated partially better binding than carbamates, we further explored SAR of the ureas analogs by synthesizing cyclohexyl, cyclopropyl and phenyl urea derivatives. The cyclohexyl urea analog demonstrated a =1.3μM with an EC=16μM whereas the cyclopropyl analog demonstrated a binding activity =0.75μM and EC=6.0μM. The phenyl urea analog had a =0.95μM a similar activity as cyclopropyl derivative but demonstrated a better cellular activity (EC=2.4μM). A close analysis of Table 1 showed that the phenethyl amide derivative and phenyl urea analog were the more active compounds with enzyme binding less than 1μM. To further improve binding in this series we decided to evaluate the SAR by incorporating α-methylbenzyl urea present in (). This was also observed as the desirable group in identification of . Concomitant to this modification we evaluated the effect of modification of the P, P and P-capping groups. Introduction of α-methylbenzyl urea had a profound effect on the binding activity of these inhibitors. α-methylbenzyl urea analog with bicyclic imide cap and P cyclopropylmethyl group resulted in compound with =0.25μM and EC=1.1μM. Replacement of bicyclic P cap with dimethylcyclohexylimide cap resulted in compound with =0.20μM similar in activity to compound and five fold improvement in activity compared to phenylurea We next evaluated the effect of modification of the P group and its capping. Incorporation of methylsulfonamide derived cap with -propyl P residue resulted in compound with =0.11μM and EC=0.7μM; a 10-fold improvement in binding compared to This was the first compound with sub micro-molar cellular activity in this series of inhibitors. Introduction of pyridylsulfonamide derived P cap with P cyclohexyl glycine and P propyl residue resulted in compound with =0.23μM a two fold loss in binding compared to methylsulfonamide derivative .