Discovery of Pyrrolidine Sulfonamides as Selective and Orally Bioavailable Antagonists of Transient Receptor Potential Vanilloid-4 (TRPV4)

Abstract

A novel series of pyrrolidine sulfonamide transient receptor potential vanilloid-4 (TRPV4) antagonists was developed by modification of a previously reported TRPV4 inhibitor (1). Several core-structure modifications were identified that improved TRPV4 activity by increasing structural rigidity and reducing the entropic energy penalty upon binding to the target protein. The new template was initially discovered as a minor regio-isomeric side product formed during routine structure–activity relationship (SAR) studies, and further optimization resulted in highly potent compounds with a novel pyrrolidine diol core. Further improvements in potency and pharmacokinetic properties were achieved through SAR studies on the sulfonamide substituent to give an optimized lead compound GSK3395879 (52) that demonstrated the ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. GSK3395879 is a tool for studying the biology of TRPV4 and an advanced lead for identifying new heart failure medicines.

Design and Optimization of an Acyclic Amine Series of TRPV4 Antagonists by Electronic Modulation of Hydrogen Bond Interactions

“…Notably, identification of conformationally rigid scaffolds that can appropriately display two aryl groups has been a key feature in optimizing activity of related TRPV4 inhibitors. 10,12,14,15 Acyclic amine 6 was a promising lead for additional optimization displaying suitable TRPV4 antagonist activity (pIC 50 = 7.3), moderate lipophilicity (Ch.LogD = 4.5), and high aqueous solubility (CLND = 381 μM) (Figure 4). When assessed in rats, 6 exhibited exceptional pharmacokinetic properties, including long IV MRT (7.5 h), low IV CL (4.3 mL/min/kg), and high oral bioavailability (85%).…”

“…Reagents and building blocks were either purchased and used as is or synthesized as described below. The following experimental studies were conducted as described previously: TRPV4 assays and rat pharmacokinetics; 12 Ch.LogD and chemiluminescent nitrogen detection (CLND) solubility assay; 19 and calculated projected human doses. 14 2,4-Dichloro-N-(4-(4-cyano-3-fluorophenoxy)-3-hydroxybutyl)benzenesulfonamide (2).…”

“…N-(3-Amino-4-(4-cyano-3-fluorophenoxy)butyl)-3-chlorobenzenesulfonamide (10). Compound 10 was prepared analogously to compound 9 and was purified using HPLC (20−60%) to afford 10 (50.5 mg, 51%) as a sticky light orange solid: 1 H NMR (400 MHz, methanol-d 4 ) δ 7.87 (t, J = 1.76 Hz, 1H), 7.81 (td, J = 1.44, 13 (S)-N-(3-Amino-4-(4-cyano-3-fluorophenoxy)butyl)-4-(trifluoromethyl)benzenesulfonamide (12). To a mixture of 62 (0.125 g, 0.387 mmol) in DCM (1.6 mL) and water (1.6 mL) was added K 2 CO 3 (0.134 g, 0.966 mmol) and 4-(trifluoromethyl)benzene-1sulfonyl chloride (0.095 g, 0.387 mmol).…”

“…A backup program to GSK2798745 was implemented to identify second-generation TRPV4 drug candidates and ensure a full exploration of potential clinical indications. The advanced lead GSK3395879 was identified but could not be progressed due to suboptimal pharmacokinetic properties and poor solubility . Several lines of research were undertaken to resolve the issues limiting GSK3395879 that led to potential candidates (e.g., GSK3491943 and GSK3527497) centered around the pyrrolidine aryl sulfonamide core. − Herein, we communicate a structurally related acyclic amine aryl sulfonamide subseries concurrently explored as part of the backup efforts.…”

Identification, Synthesis, and Characterization of a Major Circulating Human Metabolite of TRPV4 Antagonist GSK2798745

“…GSK2798745 (Figure ), a potent, selective, and orally bioavailable antagonist of the transient receptor potential vanilloid 4 (TRPV4) ion channel, was recently under clinical evaluation for the treatment of cardiac and respiratory diseases. − TRPV4 antagonists were postulated to hold promise as investigational medicines for cardiac and respiratory diseases because they prevent and resolve pulmonary edema in heart failure models and attenuate lung damage induced by chemical agents. − Preclinical studies indicated that GSK2798745 was subject to hepatic metabolism with several oxidative metabolites observed upon incubation with human hepatocytes. To elucidate the human metabolites of GSK2798745, plasma samples from healthy volunteers receiving a single 12.5 mg oral dose of drug (clinical study TR4117387, NCT02119260) were pooled and analyzed by UPLC-MS-MS and LC-MS.…”