Discovery of GSK3527497: A Candidate for the Inhibition of Transient Receptor Potential Vanilloid-4 (TRPV4)

Abstract

GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.

TRPV4: A Physio and Pathophysiologically Significant Ion Channel

“…Like many other TRP channels, TRPV4 is a polymodal protein activated by temperatures around 27 • C, hypoosmotic conditions, and mechanical stress [22,23], and blocked or antagonized by GSK3527497 [57], GSK205 [58], derivates of GSK205 [28], ruthenium red [59], and Gd 3+ (which has also been shown to block stretch-activated channels in bacteria) [58,60], RN-1734 [61], and RN-9893 [62]. Ligands for this channel include plant chemicals such as bis-andrographolide from Andrographis paniculate [63]; phorbol derivatives (i.e., 4α-phorbol 12,13-didecanoate or 4αPDD [53]), the flavonoid apigenin [64], and the widely used synthetic agonist GSK1016790A [65].…”

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%).…”

“…Of interest, we have observed similar SAR in a separate chemotype, which also contains an aryl nitrile functionality that is critical for its TRPV4 antagonist activity. [8][9][10]14 We hypothesized that the cyano group may engage in a specific H-bonding interaction with TRPV4 (Figure 7), which would be akin to those reviewed by Fleming et al 27 To test this hypothesis, a series of 3-cyano-6-substituted phenyl ether analogs (31−35; Table 5) were synthesized and assessed for their ability to bind to TRPV4. Electron-donating groups (e.g., NH 2 ) para to the 3-CN group resulted in enhanced potency, while electron-withdrawing groups (e.g., Cl) reduced activity.…”

“…Although 36 has a higher CL and lower DNAUC relative to 21, it has exceptional MRT and oral bioavailability. As a result, 36 exhibits a promising projected human dose 14 of 71 mg once a day, designating it an advanced TRPV4 inhibitor.…”

Ca2+ Signaling by TRPV4 Channels in Respiratory Function and Disease

“…Inhibitors of TRPV4 channels range from the unspecific compound ruthenium red to more specific blockers, like RN-1734 [62], RN-9893 [63], Crotamin [64], and HC-06704753 [65], with a high therapeutic potential [52]. Most interestingly a hydroxyazetidine TRPV4 inhibitor with a very low half maximal inhibitory concentration (IC 50 ) was effective to reverse agonistic effects in rat bladder but failed in other efficacy studies (reviewed in Reference [52]), while another (GSK2798745) is the first TRPV4 antagonist to reach clinical trials [66]. A selection of TRPV4 modulators, their specificity, and their prospective therapeutic options are shown in Table 1.…”