Development of CXCR3 antagonists. Part 3: Tropenyl and homotropenyl-piperidine urea derivatives

Watson, Robert J.; Allen, Daniel R.; Birch, Helen; Chapman, Gayle A.; Galvin, Frances; Jopling, Louise A.; Knight, Roland L.; Meier, Dorica; Oliver, Kathryn M.; Meissner, Johannes; Owen, David A.; Thomas, Elizabeth J.; Tremayne, Neil; Williams, Sophie C.

doi:10.1016/j.bmcl.2007.10.109

Cited by 32 publications

(18 citation statements)

References 20 publications

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“…Compound 27 has affinities of 16 and 227 nm for human and murine CXCR3 ([ 35 S]-GTPgS), [102] respectively, whereas some compounds of the related later-stage tropanyl class reveal a 3-4-fold preference for human CXCR3. [105] A systematic study on other antagonist classes (AMG487, NBI-74330, 5, and 50) shows a similar fourfold higher affinity for human and rhesus macaque CXCR3 compared to rat or mouse CXCR3. [86] Clearly, there is a slight CXCR3 species difference but it is believed that it does not represent a serious hurdle for future CXCR3 drug discovery efforts.…”

Section: Modulation Of Cxcr3 By Nonpeptidergic a C H T U N G T R E N mentioning

confidence: 99%

“…Notably, a high selectivity for CXCR3 in a panel of 50 receptors was disclosed for 30. [105] With the novel (homo)tropanyl-type structural elements at hand, replacement of the urea group was revisited. [106] This resulted in the discovery of quinoline-based antagonists (31).…”

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confidence: 99%

“…A second and seemingly more successful approach focused on the spacer and (À)myrtenyl group in 27. [105] One hundred compounds with myrtenyl replacements were prepared, affording terminal piperidinylamides (29) as pharmacokinetically more favourable compounds. Subsequent modelling studies suggested that a homotropenylamide would spatially better resemble the myrtenyl group in 27 than an unsub-866 www.chemmedchem.org stituted piperidinylamide in 29.…”

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confidence: 99%

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Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

et al. 2008

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The CXCR3 chemokine receptor was first discovered in 1996 and has been shown to play an important role in several diseases, most of which are related to inflammation. This review describes in detail the development of small CXCR3 ligands and their therapeutic potential. Classes of CXCR3 antagonists with strikingly variable core structures have emerged. Some of these compounds have confirmed the beneficial role of CXCR3 antagonism in animal models of disease. One of the compounds, AMG487, progressed to Phase II clinical trials but has been withdrawn because of lack of efficacy. New antagonist classes are being developed to reveal the full therapeutic potential of CXCR3.

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Section: Modulation Of Cxcr3 By Nonpeptidergic a C H T U N G T R E N mentioning

confidence: 99%

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Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

et al. 2008

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“…Increased microsomal stability and low CYP inhibition were achieved (e.g., 13: clearance ¼ 2.8 ml min À1 kg À1 ). The second approach focused on the piperidine spacer and concomitantly revisited the (À)-myrtenyl group in 12 [76]. Certain amides, most notably a homotropenyl amide, could replace the (À)-myrtenyl group, with the clear bonus of having improved pharmacokinetic properties.…”

Section: 31mentioning

confidence: 99%

Therapeutic Targeting of the CXCR3 Receptor

Esch

Leurs

2010

Methods and Principles in Medicinal Chemistry

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A search for T lymphocyte-specific chemokine receptors led to the discovery of the CXCR3 receptor in 1996. A novel cDNA was isolated from a human CD4 þ T cell library and the encoded GPCR proved to have affinity for chemokines [1]. Further work revealed that CXCR3 consists of 368 amino acids which assemble in a typical seven-transmembrane a-helical architecture. Chapter 2 has described in detail the structural characteristics of the chemokine receptor family and CXCR3 fits this general picture. CXCR3 exhibits typical structural motifs for GPCRs, such as the conserved DRY motif, the NPxxYx 5,6 F motif and cysteine residues in the first and second extracellular loops [2]. Also, like most chemokine receptors, CXCR3 has additional cysteine residues in the N-terminus and third extracellular loop. The threonine and serine residues in the intracellular C-terminal tail are potential sites for phosphorylation by receptor-or second messenger-regulated kinases [1, 3].CXCR3 receptors are found on activated Th1 lymphocytes, blood T cells and on a small proportion of B cells and natural killer cells [1,4,5]. CXCR3 signaling occurs preferably through pertussis toxin-sensitive Ga i proteins and involves several downstream processes such as mediation of chemotaxis, induction of calcium flux and activation of kinases such as p44/p42 MAPK and Akt [1, 3,6]. The endogenous agonists for CXCR3 are CXC chemokines CXCL9, CXCL10 and CXCL11, which were traditionally called Mig, IP-10 and I-TAC/IP-9, respectively [1, 7-10]. Of these, CXCL11 has the highest potency and efficacy on CXCR3 [1,[7][8][9][10][11]. Several reports exist on the interaction of other CXCL chemokines with CXCR3, most notably CXCL13 [12] and CXCL4 [13]. Generally, a chemokine is considered to bind to the N-terminus and extracellular loops of a chemokine receptor. Activation is thought to occur through interaction of the N-terminus of the chemokine with the transmembrane domains of the receptor [14,15]. Indeed, manipulations at the N-terminal amino acids of CXCL10 or CXCL11 can change it from a CXCR3 agonist into a CXCR3 antagonist [16][17][18][19].

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“…Recent reports indicate that there is a significant interest for the identification of small-molecule antagonists of CXCR3 [10,11]. 4-N-Aryl- [1,4] diazepane ureas were found to constitute a promising series of functional antagonists of CXCR3 that could be developed into new therapeutic agents for the treatment of inflammatory disorders such us rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and diabetes [12].…”

Section: Introductionmentioning

confidence: 99%