Structure–activity relationships of novel, highly potent, selective, and orally active CCR1 antagonists

Squaramides as Bioisosteres in Contemporary Drug Design

“…In addition, 50 was found to have a good pharmacokinetic profile in rodents (mouse t 1/2 = 2.3 h, rat t 1/2 = 2.6 h) and in vivo studies in mice were able to show a reduction in arthritis score at 50 mg/kg dose. 102 A final interesting example may be seen in a series of amino hydrazines (e.g., 52) disclosed by Chen et al in 2009 (Figure 20). 104 In addition to showing high functional IC 50 values and potent inhibition, many of those reported also showed excellent selectivity toward CXCR2 over CXCR1 (∼80-fold for the best example).…”

“…The introduction of the choline salt was able to significantly increase solubility in simulated gastric fluid (pH 1.2) from 0.001 to 8.018 mg/mL. 100 In 2007, Xie et al 102 reported on the design of a small library of novel squaramide inhibitors (e.g., 50; see Figure 19) of another member of the chemokine receptor family, C−C chemokine receptor type 1 (CCR1), based on a previously reported inhibitor, BX-471 (51). 103 Compared to BX-471, the most potent direct squaryl diamide analogue (50; see Figure 19) was found to possess remarkable antagonist activity against human CCR1, with greater than 500-fold selectivity over related CCR2, CCR3, CCR4, and CCR5.…”

“…179 The best performing of those examined (97) not only showed good potency against VLA-4 but also a low isolated perfused rat liver (IPRL) rate constant of 0.1 k hr −1 , which indicated that this analogue was not rapidly purged. 173 A further example illustrating the use of squaramides as bioisosteres of the amide group may be seen in work by Xie et al 102 The potent CCR1 antagonist (50), which was discussed here previously as a direct urea bioisostere of BX-471 (51; see Figure 19), may also be identified as a mimic of a closely related amide (100), described by Revesz et al in 2005 (Figure 38). 180 HDAC Inhibitors.…”

“…180 HDAC Inhibitors. In 2018, Fournier et al 181,182 reported on squaramide analogues (101) of histone deacetylase (HDAC) inhibitor vorinostat (102), developed by Merck Ltd. in the mid 2000s and used for the treatment of cutaneous T-cell lymphoma (Figure 39). 183,184 While effective, the clinical use of 102 (as well as other HDAC inhibitors) is limited by issues of cardiotoxicity.…”

Targeting CCR1

“…The molecule was specific for CCR1 however no in vivo data or pharmacokinetic properties were presented. In a second approach, Tanabe described the design of a novel series of CCR1 antagonists based on the structure of BX 471 [96]. Their approach was to replace the urea moeity of the compound, which is dispensable, with diaminocyclobutenedione.…”