From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: The discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis

Santella, Joseph B.; Gardner, Daniel S.; Yao, Wenqing; Shi, Chongsheng; Reddy, P. Ganapati; Tebben, Andrew J.; Delucca, George V.; Wacker, Dean A.; Watson, Paul S.; Welch, Patricia; Wadman, Eric; Davies, Paul; Solomon, Kimberly A.; Graden, Dani M.; Yeleswaram, Swamy; Mandlekar, Sandhya; Kariv, Ilona; Decicco, Carl P.; Ko, Soo S.; Carter, Percy H.; Duncia, John V.

doi:10.1016/j.bmcl.2007.11.067

Cited by 29 publications

(16 citation statements)

References 16 publications

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“…Compared to the corresponding propyl-linked compounds 23c and 23d, the analogues 26b and 26d had significantly increased antagonizing effects on eosinophil chemotaxis, with IC 50 values of 0.034 and 0.010 nM, respectively, as compared to 25 nM for 23c and 3.2 nM for 23d. 54,[56][57][58] An interesting result was that the correlation between binding IC 50 values and functional effects was higher for the phenyl ureas substituted with H-bond acceptors or heterocycles than for the other substitutions. The reason for the apparent disconnection between CCR3 binding affinity and antagonizing activity was hypothesized to result from different affinities for different receptor conformational states that are involved in the various functional activities.…”

Section: E (N-ureidoalkyl)benzylpiperidines and N-arylalkylpiperidinmentioning

confidence: 95%

“…In the series of compounds 28 (Table VI), 58 the cyclohexyl linker was replaced by various substituted propyl linkers in an attempt to obtain the same conformational rigidity as present in the trans-1,2-disubstituted cyclohexyl rings while improving selectivity for CCR3. This was done because it was thought that the superior effect of cyclohexyl-linked antagonists on chemotaxis as compared to the acyclic propyl-linked analogues was (partially) caused by this rigidity.…”

Section: E (N-ureidoalkyl)benzylpiperidines and N-arylalkylpiperidinmentioning

confidence: 99%

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Small molecule antagonists for chemokine CCR3 receptors

Willems

IJzerman

2010

Medicinal Research Reviews

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The chemokine receptor CCR3 is believed to play a role in the development of allergic diseases such as asthma, atopic dermatitis, and allergic rhinitis. Despite the conflicting results that have been reported regarding the importance of eosinophils and CCR3 in allergic inflammation, inhibition of this receptor with small molecule antagonists is thought to provide a valuable approach for the treatment of these diseases. This review describes the structure-activity relationships (SAR) of small molecule CCR3 antagonists as reported in the scientific and patent literature. Various chemical classes of small molecule CCR3 antagonists have been described so far, including (bi)piperidine and piperazine derivatives, N-arylalkylpiperidine urea derivatives and (N-ureidoalkyl)benzylpiperidines, phenylalanine derivatives, morpholinyl derivatives, pyrrolidinohydroquinazolines, arylsulfonamides, amino-alkyl amides, imidazole- and pyrimidine-based antagonists, and bicyclic diamines. The (N-ureidoalkyl)benzylpiperidines are the best studied class in view of their generally high affinity and antagonizing potential. For many of these antagonists subnanomolar IC(50) values were reported for binding to CCR3 along with the ability to effectively inhibit intracellular calcium mobilization and eosinophil chemotaxis induced by CCR3 agonist ligands in vitro.

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Section: E (N-ureidoalkyl)benzylpiperidines and N-arylalkylpiperidinmentioning

confidence: 95%

Section: E (N-ureidoalkyl)benzylpiperidines and N-arylalkylpiperidinmentioning

confidence: 99%

Small molecule antagonists for chemokine CCR3 receptors

Willems

IJzerman

2010

Medicinal Research Reviews

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“…Researchers at Bristol-Myers Squibb (BMS) identi- fied a series of arylureas, exemplified by compound 13, as potent CCR3 antagonists (Fig. (6)) [71]. Replacement of the propyl linker of 13 with a cyclohexyl spacer (compound 14) did not influence the CCR3 binding affinity but led to a 300-fold enhancement in the chemotaxis inhibitory activity.…”

Section: Chemokine Receptor 3 (Ccr3) Antagonistsmentioning

confidence: 99%

“…The first section provides an overview of reports where the authors have successfully minimized CYP2D6 inhibition during LO and reported significant structure activity relationships (SAR) at CYP2D6. These articles cover a wide range of therapeutic targets including dipeptidyl peptidase IV (DPP-4) inhibitors [68], CXC chemokine receptor 3 (CXCR3) antagonists [69], human urotensin-II (hU-II) antagonists [70], CC chemokine receptor 3 (CCR3) antagonists [71][72][73], monoamine reuptake inhibitors [74][75][76][77], kappa opioid receptor agonists [78,79], sodium channel blockers [80], 20-HETE synthase inhibitors [81,82], CB2 receptor agonists [83], H3 receptor antagonists [84], melanin-concentrating hormone receptor-1 (MCH-R1) antagonists [85], and chemokine CCR5 receptor antagonists [86].…”

Section: Survey Of Medicinal Chemistry Tactics Used To Reduce Cyp2d6 mentioning

confidence: 99%

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Medicinal Chemistry Strategies to Reduce CYP2D6 Inhibitory Activity of Lead Candidates

Bourdonnec¹,

Leister²

2009

CMC

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Among the various human cytochrome P450s (CYP450s) that catalyze the biotransformation of xenobiotics, CYP450 2D6 (CYP2D6) is one of the most important based on the number and wide variety of its drug substrates. CYP2D6 shows a high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences its expression and function. A number of drugs have been clinically implicated in major drug-drug interactions (DDI) via CYP2D6 inhibition. In order to avoid or minimize issues related to CYP2D6-mediated DDIs, pharmaceutical companies routinely screen for potential CYP2D6 liability of lead candidates in the early stage of the drug discovery process. This review summarizes the medicinal chemistry tactics employed to mitigate inhibitory activity at CYP2D6, identified through an extensive literature survey covering the 1998-2008 period.

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A Configurational Switch Based on Iridium‐Catalyzed Allylic Cyclization: Application in Asymmetric Total Syntheses of Prosopis, Dendrobate, and Spruce Alkaloids

Gnamm

Brödner

Krauter

et al. 2009

Chemistry A European J

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A method for the stereoselective synthesis of 2,6-disubstituted piperidines has been developed that is based on the use of an intramolecular iridium-catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2-vinylpiperidines with enantiomeric excesses (ee) of greater than 99%. As applications, total syntheses of piperidine alkaloids have been elaborated, most often by using Ru-catalyzed cross-metatheses as a key step for introduction of a side chain. Asymmetric total syntheses of the prosopis alkaloids (+)-prosopinine, (+)-prosophylline, (+)-prosopine, and of the dendrobate alkaloid (+)-241D and its C6 epimer are described.

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From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: The discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis

Cited by 29 publications

References 16 publications

Small molecule antagonists for chemokine CCR3 receptors

Small molecule antagonists for chemokine CCR3 receptors

Medicinal Chemistry Strategies to Reduce CYP2D6 Inhibitory Activity of Lead Candidates

A Configurational Switch Based on Iridium‐Catalyzed Allylic Cyclization: Application in Asymmetric Total Syntheses of Prosopis, Dendrobate, and Spruce Alkaloids

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