Core Replacements in a Potent Series of VEGFR-2 Inhibitors and Their Impact on Potency, Solubility, and hERG

Abstract

Anti-VEGF therapy has been a clinically validated treatment of age-related macular degeneration (AMD). We have recently reported the discovery of indole based oral VEGFR-2 inhibitors that provide sustained ocular retention and efficacy in models of wet-AMD. We disclose herein the synthesis and the biological evaluation of a series of novel core replacements as an expansion of the reported indole based VEGFR-2 inhibitor series. Addition of heteroatoms to the existing core and/or rearranging the heteroatoms around the 6−5 bicyclic ring structure produced a series of compounds that generally retained good on-target potency and an improved solubility profile. The hERG affinity was proven not be dependent on the change in lipophilicity through alteration of the core structure. A serendipitous discovery led to the identification of a new indole-pyrimidine connectivity: from 5-hydroxy to 6-hydroxyindole with potentially vast implication on the in vitro/in vivo properties of this class of compounds. KEYWORDS: Vascular endothelial growth factor receptor 2, VEGF, KDR, bicyclic core, scaffold morphing, AMD T he current approved therapies for the treatment of wet or neovascular AMD are the anti-VEGF-A antibody ranibizumab, the anti-VEGF-A aptamer pegaptanib, and the anti-VEGF-A trap fusion protein aflibercept. Each of these wet-AMD treatments must be delivered by intravitreal injections, and 60 percent of patients do not experience a clinically significant gain of visual acuity (≥15 letters). 1 Based on this we have envisioned an opportunity for orally available inhibitor of the receptor tyrosine kinase (RTK) VEGFR-2 (KDR, Flt-1) to provide an alternative wet-AMD treatment paradigm. The role of VEGF-A in the regulation of angiogenesis is well established, and although, new vessel growth and maturation are highly complex processes, requiring the sequential activation of a series of receptors by numerous ligands, VEGF-A signaling often represents a critical rate-limiting step. 2 VEGF-A promotes growth of vascular endothelial cells and is also known to induce vascular leakage. Ocular VEGF-A levels are increased in neovascular diseases of the retina such as neovascular AMD. 3,4 We have recently disclosed the medicinal chemistry efforts around the indole-pyrimidine series of VEGFR-2 inhibitors 5 where several approaches were taken toward modulation of ontarget potency, solubility, pk, and in vivo efficacy. This was accomplished by focusing on the optimization of the two extremities of the molecules: the urea and the pyrimidine. 5 Herein, we focus on the modification/replacement of the

The design and synthesis of potent benzimidazole derivatives via scaffold hybridization and evaluating their antiproliferative and proapoptotic activity against breast and lung cancer cell lines

“…Moreover, heteroatoms are frequently introduced into flat aromatic rings to lower lipophilicity, hence improving the aqueous solubility and overall developability of therapeutic candidates. 31 This is clearly observed in the designed compounds based on ADME in silico studies.…”

“…17 Ligand hybridization and core morphing and redesigning have been successfully employed for the discovery of novel VEGFR2 inhibitors. 21,31,45 Herein, core scaffold expansion using heterocyclic systems such as imidazole, thiazole, pyridazine, and quinazoline was employed for generating potent and selective VEGFR2 inhibitors. Molecular modeling studies of compounds 17, 18, and 19 unveiled that these molecules are bound to the hinge region in an ATP-competitive mode, with the benzimidazotriazine core undergoing bidentate H-bonding with Cys919 and the Glu917 backbone, and these are the predominant forces providing the inhibitor activity (Fig.…”

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

“…Anderson and co‐workers recently reported the discovery of indole‐based oral VEGFR‐2 inhibitors with efficacy in models of AMD . Addition of heteroatoms to the existing core or rearranging the heteroatoms around the 6‐5 bicyclic ring produced a series of inhibitors that retained good on‐target potency and an improved solubility profile . Anderson and co‐workers investigated the effect of introduction of heteroatoms in the 6–5 bicyclic aromatic on its potency against VEGFR‐2.…”

I2/FeCl3 Promoted Cascade Reaction of 4‐Quinazolinone, Pyridine, and Chalcone for the Synthesis of Indolizines

“…Indolizine skeleton also founds in mammals [3] . It possess plethora of biological and therapeutic applications like anti‐fungal, [4] anti‐inflammatory, [5] anti‐oxidant, [6] anti‐cancer, [7] anti‐HIV, [8] anti‐viral, [9] antibacterial [10] in addition to this it is also used as fluorescence [11]…”

“…[2] Indolizine skeleton also founds in mammals. [3] It possess plethora of biological and therapeutic applications like anti-fungal, [4] anti-inflammatory, [5] antioxidant, [6] anti-cancer, [7] anti-HIV, [8] anti-viral, [9] antibacterial [10] in addition to this it is also used as fluorescence. [11] Among the indolizine scaffolds, mainly 3-alkyl and 3-aryle Indolizine (Figure 1) shows significant biological activities, which are used as 5-hydroxytryptamine (5-HT3) receptor [12] antagonist, 15-lipoxygenase, [13] phosphoinositide 3-kinase, [14] phosphodiesterase-4 (PDE-4), [15] tumor necrosis factor (TNF-α) inhibitors [16] as orexin receptor, [17] human group (IIa) secreted phospholipase A2 (sPLA2), [18] sodium-glucose cotransporter-2 (SGLT2).…”