We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.
Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.
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.
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