ABSTRACT
Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.
Subject(s)
Aza Compounds/pharmacology , Indazoles/pharmacology , Receptors, CCR1/antagonists & inhibitors , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Dose-Response Relationship, Drug , Drug Design , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Molecular Structure , Receptors, CCR1/metabolism , Structure-Activity RelationshipABSTRACT
The prognosis of patients with gastroesophageal junction (GOJ) adenocarcinoma depends mainly on the clinical staging, as described by the new AJCC8 (American Joint Committee on Cancer 8th edition). Evidence suggests that peripheral blood neutrophil-to-lymphocyte ratio (NLR) may be of prognostic significance in patients with upper gastrointestinal cancers. We examined the prognostic significance of NLR in the era of the new AJCC8 staging system. In this single-centre cohort study, retrospective data on patients with operable GOJ adenocarcinoma treated with perioperative chemotherapy were analysed. The prognostic significance of baseline NLR in combination with AJCC8 clinical staging and other patient characteristics was examined for both time-to-progression (TTP) and overall survival (OS). Of 316 patients, 245 (77.5%) underwent radical surgery. Fifty-one patients (16.2%) developed unresectable disease due to early disease progression. NLR was the only baseline factor independently associated with the development of early disease progression. AJCC8 clinical staging was significantly associated with TTP and OS. In addition, NLR ≥ 3 was predictive of poorer TTP (p = 0.001) and OS (p = 0.002), confirmed in multivariate Cox-regression analysis. NLR ≥ 3 was prognostic, especially in patients with clinical stage III for TTP (p = 0.006) and OS (p = 0.025) and in patients with clinical stage IVA for OS (p = 0.017). NLR significantly improved the prognostic classification of patients by different AJCC8 clinical stages, with a c-index improved from 0.554 to 0.592 (p < 0.001). NLR was confirmed to be an independent prognostic factor in this cohort and could be used in combination with AJCC8 clinical staging to improve the baseline prognostic stratification of patients with newly diagnosed resectable GOJ adenocarcinoma.
Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Lymphocytes/cytology , Neoplasm Staging , Neutrophils/cytology , Adenocarcinoma/diagnosis , Adenocarcinoma/epidemiology , Adenocarcinoma/pathology , Aged , Disease Progression , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/epidemiology , Esophageal Neoplasms/pathology , Female , Humans , Leukocyte Count , Male , Middle Aged , Neoplasm Staging/methods , Neoplasm Staging/standards , Prognosis , Retrospective Studies , Time FactorsABSTRACT
Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.
