The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032)

Abstract

The discovery of asunaprevir (1) began with the concept of engaging the small and well-defined S 1 ' pocket of the hepatitis C virus (HCV) NS3/4A protease that was explored in the context of tripeptide carboxylic acid-based inhibitors. A cyclopropyl-acyl sulfonamide moiety was found to be the optimal element at the P 1-P 1 ' interface enhancing the potency of carboxylic acid-based prototypes by 10-to >100-fold, dependent upon the specific background. Optimization for oral bioavailability identified a 1-substituted isoquinoline-based P 2 * element that conferred a significant exposure advantage in rats compared to the matched 4-substituted quinoline isomer. BMS-605339 (30) was the first cyclopropyl-acyl sulfonamide derivative advanced into clinical trials that demonstrated dose-related reductions in plasma viral RNA in HCV-infected patients. However, 30 was

Applications of Bioisosteres in the Design of Biologically Active Compounds

“…66,67 An X-ray cocrystal structure of BMS-605339 (27) bound to a GT1b NS3/4A construct provided insight into the potency enhancing effects of the acyl sulfonamide moiety, which is intimately engaged with all elements of the catalytic machinery of the enzyme, as depicted in Figure 4. 66,67 The negative charge was calculated to preferentially reside on the nitrogen atom of the acyl sulfonamide and engage the protonated imidazole heterocycle of the catalytic His 57 in a salt bridge interaction. The carbonyl oxygen atom and both sulfonamide oxygen atoms were Hbonded to the N−H of Gly 137 that, along with Ser 138 , forms the oxyanion hole of the enzyme.…”

“…The addition of a single carbon atom is less detrimental with a modest 4- to 7-fold reduction in potency for the cyclobutyl homologue 23 , while the cyclopentyl derivative 24 is comparable with 21 and the cyclohexyl 25 is less potent than both acid 19 and the methanesulfonamide 20 in the enzyme assay. Interestingly, the phenyl-substituted homologue 26 retains significant enzyme and replicon inhibitory activity that is comparable with the cyclobutyl derivative 23 , despite the increased size. , An X-ray cocrystal structure of BMS-605339 ( 27 ) bound to a GT1b NS3/4A construct provided insight into the potency enhancing effects of the acyl sulfonamide moiety, which is intimately engaged with all elements of the catalytic machinery of the enzyme, as depicted in Figure . , The negative charge was calculated to preferentially reside on the nitrogen atom of the acyl sulfonamide and engage the protonated imidazole heterocycle of the catalytic His 57 in a salt bridge interaction. The carbonyl oxygen atom and both sulfonamide oxygen atoms were H-bonded to the N–H of Gly 137 that, along with Ser 138 , forms the oxyanion hole of the enzyme.…”

“…The carbonyl oxygen atom and both sulfonamide oxygen atoms were H-bonded to the N–H of Gly 137 that, along with Ser 138 , forms the oxyanion hole of the enzyme. In addition, one of the sulfonamide oxygen atoms engaged the side chain OH of the catalytic Ser 139 in an H-bonding interaction. ,, The cyclopropyl ring provided optimal van der Waals surface contact in the S 1 ′ pocket, which is formed by the convergence of Gln 41 , Phe 43 , Val 55 , and Gly 58 , with Phe 43 located at the base of the shallow cavity. Modeling studies suggested that conformational mobility associated with the side chain of Gln 41 could accommodate the phenyl substituent in 26 , although in an imperfect fashion. , …”

“…However, optimization of the cyclopropyl derivative 22 resulted in significantly enhanced inhibitory potency that amounted to a 40-to 50-fold advantage in the biochemical enzyme assay using a genotype 1a (GT1a) enzyme construct and 165-to 250-fold in a GT1b cell-based replicon assay. 66,67,69,70 The SARs summarized in Table 1 highlight the importance of filling the hydrophobic but rather shallow S 1 ′ enzyme subpocket and the sensitivity of this pocket to the size and shape of the sulfonamide substituent that provides an interesting exemplification of the "55% rule." 71,72 Ring-opening of the cyclopropane ring to an isopropyl substituent (21), formally the addition of just two hydrogen atoms to 20, results in a 20-fold erosion of potency, which is presumably a reflection of the relaxation of the geometrical constraints conferred by the 3-membed ring that increases the size of the substituent.…”

“…Interestingly, the phenyl-substituted homologue 26 retains significant enzyme and replicon inhibitory activity that is comparable with the cyclobutyl derivative 23, despite the increased size. 66,67 An X-ray cocrystal structure of BMS-605339 (27) bound to a GT1b NS3/4A construct provided insight into the potency enhancing effects of the acyl sulfonamide moiety, which is intimately engaged with all elements of the catalytic machinery of the enzyme, as depicted in Figure 4. 66,67 The negative charge was calculated to preferentially reside on the nitrogen atom of the acyl sulfonamide and engage the protonated imidazole heterocycle of the catalytic His 57 in a salt bridge interaction.…”