Structure–Activity Relationship (SAR) Optimization of 6-(Indol-2-yl)pyridine-3-sulfonamides: Identification of Potent, Selective, and Orally Bioavailable Small Molecules Targeting Hepatitis C (HCV) NS4B

Abstract

A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the optimal combination of substituents at the indole N-1, C-5, and C-6 positions and the sulfonamide group to limit the potential for in vivo oxidative metabolism and to achieve an acceptable pharmacokinetic profile. Compound 4t has excellent potency against the HCV 1b replicon, with an EC50 = 2 nM and a selectivity index of >5000 with respect to cellular GAPDH. Compound 4t has an overall favorable pharmacokinetic profile with oral bioavailability values of 62%, 78%, and 18% in rats, dogs, and monkeys, respectively, as well as favorable tissue distribution properties with a liver to plasma exposure ratio of 25 in rats.

Preclinical Characterization and In Vivo Efficacy of GSK8853, a Small-Molecule Inhibitor of the Hepatitis C Virus NS4B Protein

“…Cell lines stably carrying HCV replicons of genotype 1a or 1b were treated with GSK8853 at a concentration of 5ϫ or 20ϫ the EC 50 . Medium and compound were changed every 3 days until colonies started to form, at which point total RNA from each plate was isolated with TRIzol (Invitrogen) and cDNAs were generated with a High Capacity cDNA reverse transcription kit (Applied Biosciences).…”

“…In vitro resistance selection was performed by serial passage of genotype 1b (7) and 1a stable replicons in the presence of GSK8853 at concentrations 5-fold and 20-fold above the EC 50 , which were intended to model both moderate and high levels of inhibition. Analysis of the genotype 1b replicon sequence after selection revealed changes from the wild type that resulted in amino acid changes H94R, F98L, and V105M, similarly to reports of studies performed with other NS4B inhibitors (7,11,12).…”

A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates

“…In this project, two distinct sets of chemical modifications were carried out involving the benzene ring of the indole core and the N-1 substituent. 114 The first set of modifications were 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 planned in order to reduce the oxidative metabolism observed at the expense of the indole benzene ring. Towards this end, the contemporary presence of two adjacent substituents at C-5 and C-6 positions would block arene oxide formation.…”

“…Towards this end, the contemporary presence of two adjacent substituents at C-5 and C-6 positions would block arene oxide formation. 114 Fluorine atom was chosen as the the sole C-5 substituent retaining good activity in the parent indolphenyl sulfonamide series (compound 47 in Figure 17). 114 As expected, the insertion of a fluorine atom at C-5 position of the indole ring gave the equipotent compound 63 ( Figure 22A).…”

Indole, a Privileged Structural Core Motif

“…(B) C2 Activation: Zhang and co-workers 11 reported the synthesis of N-(6-(indol-2-yl)pyridine-3-sulfonamide 13 starting from the substituted indole 11. The mechanism involves the boronic acid intermediate 12.…”