BMS-605339

A review.The discovery of asunaprevir ( 1 ) began with the concept of engaging the small and well-defined S1 ' 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 P1 -P1 ' 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 P2 * 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 clin. trials that demonstrated dose-related reductions in plasma viral RNA in HCV-infected patients.However, 30 was associated with cardiac events observed in a normal healthy volunteer (NHV) and an HCV-infected patient that led to the suspension of the development program.Using a Langendorff rabbit heart model, a limited structure-cardiac liability relationship was quickly established that led to the discovery of 1 .This compound, which differs from 30 only by changes in the substitution pattern of the P2 * isoquinoline heterocycle and the addition of a single chlorine atom to the mol. formula, gave a dose-dependent reduction in plasma viral RNA following oral administration to HCV-infected patients without the burden of the cardiac events that had been observed with 30 .A small clin. trial of the combination of 1 with the HCV NS5A inhibitor daclatasvir ( 2 ) established for the first time that a chronic genotype 1 (GT-1) HCV infection could be cured by therapy with two direct-acting antiviral agents in the absence of exogenous immune-stimulating agents.Development of the combination of 1 and 2 was initially focused on Japan where the patient population is predominantly infected with GT-1b virus, culminating in marketing approval which was granted on July 4, 2014.In order to broaden therapy to include GT-1a infections, a fixed dose triple combination of 1 , 2, and the allosteric NS5B inhibitor beclabuvir ( 3 ) was developed, approved by the Japanese health authorities for the treatment of HCV GT-1 infection on Dec. 20, 2016 and marketed as Ximency .

An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = -0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.