Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, Allschwil CH-4123, Switzerland.
Published: December 2020
AI Article Synopsis
Article Abstract
The chemokine receptor CXCR7, also known as ACKR3, is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies such as neurological diseases, autoimmune diseases, and cancers. By binding and scavenging the chemokines CXCL11 and CXCL12, CXCR7 regulates their extracellular levels. From an original high-throughput screening campaign emerged hit among others. The hit-to-lead optimization led to the discovery of a novel chemotype series exemplified by the trans racemic compound . This series provided CXCR7 antagonists that block CXCL11- and CXCL12-induced ß-arrestin recruitment. Further structural modifications on the trisubstituted piperidine scaffold of yielded compounds with high CXCR7 antagonistic activities and balanced ADMET properties. The effort described herein culminated in the discovery of ACT-1004-1239 (). Biological characterization of ACT-1004-1239 demonstrated that it is a potent, insurmountable antagonist. Oral administration of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase of plasma CXCL12 concentration.
Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Institute of Urology, Anhui Medical University, Hefei, China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China. Electronic address:
Chronic prostatitis and Pelvic Pain syndrome (CP/CPPS) is an autoimmune inflammatory disease characterized by pelvic or perineal pain and infiltration of inflammatory cells in the prostate. C-X-C chemokine receptor type 7 (CXCR7) is an atypical chemokine receptor that has been shown to play a key role in inflammatory processes in prostate cancer. However, the role of CXCR7 in autoimmune prostate and immune regulation in CP/CPPS along with the mechanism of action for CXCR7 remains unclear.
Introduction: Glioblastoma is the most aggressive brain tumor, typically associated with poor prognosis. Its treatment is challenging due to the peculiar glioblastoma cell biology and its microenvironment complexity. Specifically, a small fraction of glioma stem cells within the tumor mass drives tumor growth and invasiveness by hijacking brain resident and immune cells.
Introduction: Abnormal activation of hypertrophic scar fibroblasts (HSF) plays an important role in the excessive fibrosis of hypertrophic scars (HS). However, the regulatory mechanism of HSF abnormal activation is not fully unclear. Early studies had shown that M2 macrophages were increased during scar formation.
Cardiorenal fibrosis is a common feature of chronic cardiovascular disease and recent data suggests that cytokines and chemokines may also drive fibrosis. Here we tested the hypothesis that CXCR7, a highly conserved chemokine receptor, contributes to cardiac and renal fibrosis. We generated an anti-mouse CXCR7-specific monoclonal antibody (CXCR7 mAb) and tested its anti-fibrotic actions in cardiorenal fibrosis induced using the deoxycorticosterone acetate/uni-nephrectomy (DOCA-UNX) model.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
An innovative palladium-catalyzed alkenylation of peptides and vinyl iodides has been developed. This method does not require the introduction of a directing group and uses carboxylic acid groups as endogenous directing groups. It is noteworthy that two key building blocks for the ilamycins and CXCR7 modulators were prepared using our methodology.
