Targeting CCR1

Horuk, Richard

doi:10.1002/9783527631995.ch14

Cited by 8 publications

(5 citation statements)

References 75 publications

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“…The antagonism of CCR1, a G-protein coupled receptor, in rodent models of inflammation suggests that its blockade is a viable strategy to develop anti-inflammatory drugs . Consequently, Santella and colleagues proceeded to develop a CCR1 antagonist possessing desirable properties such as (a) target affinity, (b) functional potency, (c) selectivity, (d) metabolic stability, (e) availability as a large free fraction in plasma, (f) favorable pharmacokinetics, (g) no PXR transactivation, and (h) no QT prolongation/cardiovascular effects.…”

Section: Pharmacodynamics Contribution Of a Gem-dimethyl Groupmentioning

confidence: 99%

Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry

Talele

2017

J. Med. Chem.

107

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The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p K of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.

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Section: Pharmacodynamics Contribution Of a Gem-dimethyl Groupmentioning

confidence: 99%

Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry

Talele

2017

J. Med. Chem.

107

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“…10 Preclinical studies in rodents demonstrated that CCR1 receptor blockade represents a viable strategy for the development of therapies for inflammatory disorders. 11 The BMS CCR1 program aimed to discover a small-molecule antagonist for the treatment of rheumatoid arthritis (RA). 10 The Boyden chamber assay has been used to evaluate the CCR1 inhibitor in the monocyte THP-1 background.…”

Section: Monocyte Thp-1 Chemotaxismentioning

confidence: 99%

Leveraging the IncuCyte Technology for Higher-Throughput and Automated Chemotaxis Assays for Target Validation and Compound Characterization

Chen

Ribeiro

et al. 2018

SLAS Discovery

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Chemotaxis is the directional movement of cells in response to a chemical stimulus and is vital for many physiological processes, including immune responses, tumor metastasis, wound healing, and blood vessel formation. Therefore, modulation of chemotaxis is likely to be of therapeutic benefit. Hence, a high-throughput means to conduct chemotaxis assays is advantageous for lead evaluation and optimization in drug discovery. In this study, we have validated a novel approach for a higher-throughput, label-free, image-based IncuCyte chemotaxis assay encompassing various cell types, including T cells, B cells, mouse Th17, immature and mature dendritic cells, monocyte THP-1, CCRF-CEM, monocytes, neutrophils, macrophages, and MDA-MB-231. These assays enable us to visualize chemotactic cell migration in real time and perform kinetic cell motility studies on an automated platform, thereby allowing us to incorporate the quantitative studies of cell migration behavior into a routine drug discovery screening cascade.

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“…Consequently, several chemokine signaling inhibitors have been developed, and their potential and importance as targets of anti‐inflammatory drugs have been recently summarized . Several CCR1 inhibitors such as C‐4462 (Merck, Kenilworth, NJ, USA) and BMS‐817399 (Bristol‐Myers Squibb, New York, NY, USA) entered Phase II trials for RA, but results are either unpublished or negative . However, CCX‐354 (ChemoCentryx, Mountain View, CA, USA), another CCR1 inhibitor, proved to be effective in Phase II trials for RA, albeit its current status is not known .…”

Section: Novel Targets With Anti‐inflammatory And/or Analgesic Potentmentioning

confidence: 99%

Challenges to develop novel anti‐inflammatory and analgesic drugs

Botz

Bölcskei

Helyes

2016

WIREs Nanomed Nanobiotechnol

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Chronic inflammatory diseases and persistent pain of different origin represent common medical, social, and economic burden, and their pharmacotherapy is still an unresolved issue. Therefore, there is a great and urgent need to develop anti-inflammatory and analgesic agents with novel mechanisms of action, but it is a very challenging task. The main problem is the relatively large translational gap between the preclinical experimental data and the clinical results due to characteristics of the models, difficulties with the investigational techniques particularly for pain, as well as species differences in the mechanisms. We summarize here the current state-of-the-art medication and related ongoing strategies, and the novel targets with lead molecules under clinical development. The first members of the gold-standard categories, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and opioids, were introduced decades ago, and since then very few drugs with novel mechanisms of action have been successfully taken to the clinics despite considerable development efforts. Several biologics targeting different key molecules have provided breakthrough in some autoimmune/inflammatory diseases, but they are expensive, only parenterally available, their long-term side effects often limit their administration, and they do not effectively reduce pain. Some kinase inhibitors and phosphodiesterase-4 blockers have recently been introduced as new directions. There are in fact some promising novel approaches at different clinical stages of drug development focusing on transient receptor potential vanilloid 1/ankyrin 1 channel antagonism, inhibition of voltage-gated sodium/calcium channels, several enzymes (kinases, semicarbazide-sensitive amine oxidases, and matrix metalloproteinases), cytokines/chemokines, transcription factors, nerve growth factor, and modulation of several G protein-coupled receptors (cannabinoids, purinoceptors, and neuropeptides). WIREs Nanomed Nanobiotechnol 2017, 9:e1427. doi: 10.1002/wnan.1427 For further resources related to this article, please visit the WIREs website.

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Targeting CCR1

Cited by 8 publications

References 75 publications

Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry

Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry

Leveraging the IncuCyte Technology for Higher-Throughput and Automated Chemotaxis Assays for Target Validation and Compound Characterization

Challenges to develop novel anti‐inflammatory and analgesic drugs

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