IV. Discovery of CXCR3 antagonists substituted with heterocycles as amide surrogates: Improved PK, hERG and metabolic profiles

Pharmacological Characterization of [3H]VUF11211, a Novel Radiolabeled Small-Molecule Inverse Agonist for the Chemokine Receptor CXCR3

“…The purpose of the present study was to characterize the pharmacological properties of the (radiolabeled) small-molecule CXCR3 antagonist VUF11211 from the piperazinyl-piperidine class, which contains many compounds possessing (sub)nanomolar affinities for CXCR3 (McGuinness et al, 2009;Kim et al, 2011;Shao et al, 2011;Nair et al, 2014). VUF11211 showed antagonistic behavior in CRE reporter gene-and b-arrestin recruitment assays, where it completely blocked CXCL11-induced receptor activation (Fig.…”

“…In view of the potential therapeutic interest in CXCR3 blockade in diseases like rheumatoid arthritis and allograft rejection (Wijtmans et al, 2011), many different drug discovery programs have yielded several distinct chemical classes of small-molecule compounds, including antagonists as well as a few agonists (Wijtmans et al, 2008(Wijtmans et al, , 2011, such as the 8-azaquinazolinone compounds from Amgen Inc. (AMG487, (R)-N- (1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)ethyl)-N-(pyridin-3-ylmethyl)-2-(4-trifluoromethoxy)phenyl)acetamide; Washington, D.C.) and Neurocrine Biosciences pyrimidin-2-yl)ethyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(pyridin-3-ylmethyl)acetamide; San Diego, CA), which bind to CXCR3 with affinities in the nanomolar range (Heise et al, 2005;Johnson et al, 2007;Verzijl et al, 2008). Moreover, a piperazinyl-piperidine compound class containing ligands with nanomolar CXCR3 affinities was reported by Schering Plough (now Merck Sharp & Dohme, Kenilworth, NJ) (Mcguinness et al, 2009;Kim et al, 2011;Shao et al, 2011;Nair et al, 2014).…”

Designing small molecule CXCR3 antagonists

“…Oxadiazole was found to be the most promising heterocycle in terms of maintaining CXCR3 binding activity. Subsequent synthesis of substituted oxadiazoles in an effort to replace the pyridine in the core of the molecule identified the primary amide analog 2a (SCH 546738, Figure 2) which was elected for in vivo proof-of-principle studies [39]. Subsequent dosing of SCH 546738 in mice at 40 mg/kg showed it to have significant efficacy in a collagen-induced arthritis model.…”

“…Ultimately this lead to the discovery of Compound 16e ( Figure 2) with an improved PK profile and reduced hERG activity but still retaining singledigit affinity for CXCR3 affinity [38]. Additional SAR was then carried out to replace the amide group with heterocycle surrogates, the objective being to avoid metabolic cleavage of the left-hand side amide moiety but maintain identical or improved biological profiles [39]. Oxadiazole was found to be the most promising heterocycle in terms of maintaining CXCR3 binding activity.…”

Structure–Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum In Vitro

“…Amides are utilized as ester group bioisosteres; additionally, amidation is a known strategy for reducing hERG affinity and improving aqueous solubility. , Therefore, we accordingly prepared and evaluated amides at the 4-position in the lateral phenyl group while maintaining either a 4-F or 4-CN group in the benzyl portion (Table ). However, these AST amide analogues 43 – 53 produced lower activities ( Pf NF54 IC 50 = 0.199–1.91 μM) compared to those of the ester match pairs ( 33 and 34 ) and AST, although the desired increase in solubility was achieved in some of the amides, especially those that contained water-solubilizing groups ( 43 – 46 ).…”