Novel pyrrolidine heterocycles as CCR1 antagonists

Merritt, J. Robert; James, Ray A.; Paradkar, Vidyadhar M.; Zhang, Chongwu; Liu, Ruiyan; Liu, Jinqi; Jacob, Biji; Chiriac, Camelia; Ohlmeyer, Michael J.; Quadros, Elizabeth; Wines, Pamela G.; Postelnek, Jennifer; Hicks, Catherine M.; Chen, Weiqing; Kimble, Earl F.; O’Brien, Linda; White, Nicole S.; Desai, Hema; Appell, Kenneth C.; Webb, Maria L.

doi:10.1016/j.bmcl.2010.07.082

Cited by 11 publications

(7 citation statements)

References 14 publications

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“…Using membranes from HEK_CCR1Gqi5 cells, we confirmed that AZD‐4818, BX471, CCX354, CP481715 and PS899877 are all potent inhibitors of [ 125 I]‐CCL3 binding (Figure ; Table ). In the cases of BX471, CP481715 and PS899877, our findings are similar to those previously reported with HEK cells (Anders et al ., ; Vallet et al ., ; Merritt et al ., ). We then examined the compounds using membranes from RPMI 8226 cells ( Figure ; Table ;).…”

Section: Resultsmentioning

confidence: 98%

“…Further information on chemokine receptors including CCR1 can be found at the International Union of Basic and Clinical Pharmacology (IUPHAR)/BPS website (http://www.guidetopharmacology.org/). Scientists from Berlex (now Bayer HealthCare Pharmaceuticals) provided the first small molecule antagonist for CCR1 in 1998 (Hesselgesser et al ., ), and since then, numerous inhibitors have been identified (Gladue et al ., ; Vallet et al ., ; Merritt et al ., ; ; Kerstjens et al ., ; Dairaghi et al ., ; ; Gardner et al ., ; Pennell et al ., ; Hossain et al ., ). To date, six compounds targeting CCR1 have undergone clinical trials (Table ) for multiple sclerosis, rheumatoid arthritis and chronic obstructive pulmonary disease (Gladue et al ., ; Karash and Gilchrist, ).…”

Section: Introductionmentioning

confidence: 99%

“…We focus our work on six CCR1 antagonists that were initially identified using competitive binding assays with CCL3 or CCL15 and HEK cells overexpressing recombinant human CCR1 (Table ). Previous work on these allosteric inhibitors includes (i) measurement of calcium transients; (ii) chemotaxis of leukocytes; and (iii) leukocyte up‐regulation of CD11b (Gladue et al ., ; Pease and Horuk, ; Merritt et al ., ). However, there have been limited studies with these CCR1 antagonists using assays that are more relevant to MM (Karash and Gilchrist, ).…”

Section: Introductionmentioning

confidence: 99%

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Identifying bias in CCR1 antagonists using radiolabelled binding, receptor internalization, β‐arrestin translocation and chemotaxis assays

Gilchrist

Gauntner

Fazzini

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEInvestigators have suggested that the chemokine receptor CCR1 plays a role in multiple myeloma. Studies using antisense and neutralizing antibodies to CCR1 showed that down-regulation of the receptor altered disease progression in a mouse model. More recently, experiments utilizing scid mice injected with human myeloma cells demonstrated that the CCR1 antagonist BX471 reduced osteolytic lesions, while the CCR1 antagonist MLN-3897 prevented myeloma cell adhesion to osteoclasts. However, information is limited regarding the pharmacology of CCR1 antagonists in myeloma cells. EXPERIMENTAL APPROACHWe compared several well-studied CCR1 antagonists including AZD4818, BX471, CCX354, CP-481715, MLN-3897 and PS899877 for their ability to inhibit binding of [ 125 I]-CCL3 in vitro using membranes prepared from RPMI 8226 cells, a human multiple myeloma cell line that endogenously expresses CCR1. In addition, antagonists were assessed for their ability to modulate CCL3-mediated internalization of CCR1 and CCL3-mediated cell migration using RPMI 8226 cells. As many GPCRs signal through β-arrestin-dependent pathways that are separate and distinct from those driven by G-proteins, we also evaluated the compounds for their ability to alter β-arrestin translocation. KEY RESULTSThere were clear differences between the CCR1 antagonists in their ability to inhibit CCL3 binding to myeloma cells, as well as in their ability to inhibit G-protein-dependent and -independent functional responses. CONCLUSIONS AND IMPLICATIONSOur studies demonstrate that tissue phenotype seems to be relevant with regards to CCR1. Moreover, it appears that for CCR1 antagonists, inhibition of β-arrestin translocation is not necessarily linked to chemotaxis or receptor internalization. AbbreviationsEA, enzyme acceptor; MM, multiple myeloma; MIP-1α, macrophage inflammatory protein-1α; PEN, penicillin; STREP, streptomycin BJP British Journal of Pharmacology

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identifying bias in CCR1 antagonists using radiolabelled binding, receptor internalization, β‐arrestin translocation and chemotaxis assays

Gilchrist

Gauntner

Fazzini

et al. 2014

British J Pharmacology

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show abstract

“…Preclinical studies in rodents suggested that CCR1 blockade represents a viable strategy for the development of therapies for inflammatory disorders . Several small molecule antagonists of CCR1 have appeared in the literature, , and a number have advanced to human clinical trials (Figure ) . These include BX-471 ( 1 ) for multiple sclerosis, CP-481715 ( 2 ) for rheumatoid arthritis (RA), ,, AZD-4818 ( 3 ) for chronic obstructive pulmonary disease, and MLN-3897 ( 4 ) for RA .…”

Section: Introductionmentioning

confidence: 99%

“…Several small molecule antagonists of CCR1 have appeared in the literature, , and a number have advanced to human clinical trials (Figure ) . These include BX-471 ( 1 ) for multiple sclerosis, CP-481715 ( 2 ) for rheumatoid arthritis (RA), ,, AZD-4818 ( 3 ) for chronic obstructive pulmonary disease, and MLN-3897 ( 4 ) for RA . Unfortunately, these molecules failed to achieve their targeted clinical end points in phase 2 studies.…”

Section: Introductionmentioning

confidence: 99%