ABSTRACT
A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid. In this study we report our early optimisation studies on this hydrazide series. The new analogues had significantly improved potency in cell-based assays, increased sp3 character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention.
Subject(s)
Muscular Dystrophy, Duchenne , Animals , Hydrazines/pharmacology , Hydrazines/therapeutic use , Mice , Muscle, Skeletal/metabolism , Muscular Dystrophy, Duchenne/drug therapy , Muscular Dystrophy, Duchenne/metabolism , Structure-Activity Relationship , Up-Regulation , Utrophin/genetics , Utrophin/metabolism , Utrophin/therapeutic useABSTRACT
INTRODUCTION: The objective of this study was to look at the usefulness and cost effectiveness of intraoperative frozen section analysis (FSA) of the ureters at the time of radical cystectomy. METHODS: Pathology notes of patients undergoing radical cystectomy for primary bladder cancer between the years 2000-2015 at our institution were reviewed. RESULTS: A total of 196 ureteric specimens from 98 patients were reviewed. Of the 98 patients, 9% (n = 9) had positive ureteric margins, of which all were ≥ T2, with 44% (4 of 9) being T = 4. In all cases of positive FSA, preoperative clinical staging was ≥ T2. In cases where cancer staging was upgraded post-cystectomy, there were no cases of positive FSA. After adjusting for tumor stage in ≥ T2a, using Cox regression analysis, positive frozen section was associated with a 4.2 fold increase in overall mortality (95%CI 1.3-13.8; p = 0.02). Cost associated with FSA was AU$1,351.90 to obtain 1 positive result. CONCLUSION: Patients with positive ureteric FSA are at higher risk of mortality post cystectomy, despite excision to negative tissue. However, FSA of the distal ureters at cystectomy were unlikely to be positive unless the bladder cancer stage was ≥ T2. Hence, routine ureteric FSA may not be necessary in patients undergoing cystectomy for non-muscle invasive bladder tumors.
ABSTRACT
Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).
Subject(s)
Acetates/pharmacology , Drug Discovery , Indoleacetic Acids/pharmacology , Indoles/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Humans , Indoleacetic Acids/chemistry , Indoles/chemistry , Neutrophils/drug effectsABSTRACT
A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action. Understanding the complex SAR allowed design of potent antagonists such as potential candidate 34.
Subject(s)
Acetates/chemical synthesis , Receptors, Immunologic/agonists , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/agonists , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Acetates/pharmacology , Animals , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A hit-to-lead optimisation programme was carried out on the thiophenecarboxamide high throughput screening hits 1 and 2 resulting in the discovery of the potent and orally bioavailable IKK-2 inhibitor 22.
Subject(s)
Amides/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Amides/chemical synthesis , Animals , Binding Sites , Cell Line , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , I-kappa B Kinase , Inhibitory Concentration 50 , Ligands , Models, Molecular , Protein Array Analysis , Protein Binding , Rats , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
A Hit-to-Lead optimisation programme was carried out on the adamantane high throughput screening hit 1 resulting in the discovery of a number of potent P2X(7) antagonists.
Subject(s)
Adamantane/analogs & derivatives , Adamantane/pharmacology , Amides/pharmacology , Purinergic P2 Receptor Antagonists , Adamantane/chemical synthesis , Amides/chemical synthesis , Drug Design , Humans , Kinetics , Receptors, Purinergic P2X7 , Structure-Activity RelationshipABSTRACT
A Hit-to-Lead optimisation programme was carried out on the high throughput screening hit, the triazolethiol 1, resulting in the discovery of the potent, orally bioavailable triazolethiol CXCR2 receptor antagonist 45.
