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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 sp

Methods for the batch scale up of DABAL-Me3 promoted direct ester to amide synthesis have been demonstrated at 10–100 g scales using a tert-amide model compound. Procedures for 20 g scale couplings in standard laboratory glassware and up to 0.1 kg in industry-standard jacketed glass reactors in near quantitative yields are given. A derivative of the anticancer agent Imatinib (Gleevec) has been synthesized on a 26 g scale (98% yield, >98% purity) establishing DABAL-Me3 as a potential alternative for the synthesis of amides in API scale preparations. Continuous flow methodology provides a method for larger scales (productivities of >50 g h–1). In addition, nitriles were coupled to primary amines and hydrazines with DABAL-Me3, resulting in the clean formation of free amidines (16 examples) and amidrazones.

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.

ReactIR studies of mixtures of AlEt3 (A) and cyclohex-2-en-1-one (CX)\ud in Et2O indicate immediate formation of the Lewis acid−base complex CX·A at −40\ud °C (K = 12.0 M−1\ud , ΔG°react = −1.1 kcal mol−1\ud ). Copper(I) catalysts, derived from\ud precatalytic Cu(OAc)2 (up to 5 mol %) and (R,S,S)-P(binaphtholate){N(CHMePh)2}\ud (Feringa’s ligand (L), up to 5 mol %) convert CX·A (0.04−0.3 M) into its 1,4-addition\ud product enolate (E) within 2000 s at −40 °C. Kinetic studies (ReactIR and chiral GC)\ud of CX·A, CX, and (R)-3-ethylcyclohexanone (P, the H+ quenching product of enolate\ud E) show that the true catalyst is formed in the first 300 s and this subsequently\ud provides P in 82% ee. This true catalyst converts CX·A to E with the rate law\ud [Cu]1.5[L]\ud 0.66[CX·A]\ud 1 when [L]/[Cu] ≤ 3.5. Above this ligand ratio inhibition by\ud added ligand with order [L]\ud −2.5 is observed. A rate-determining step (rds) of\ud Cu3L2(CX·A)2 stoichiometry is shown to be most consistent with the rate law. The\ud presence of the enolate in the active catalyst best accounts for the reaction’s induction period and molecularity as [E] ≡ [CX·A].\ud Catalysis proceeds through a “shuttling mechanism” between two C2 symmetry related ground state intermediates. Each turnover\ud consumes 1 equiv of CX·A, expels one molecule of E, and forms the new Cu−Et bond needed for the next cycle. The observed\ud ligand (L) inhibition and a nonlinear ligand L ee effect on the ee of P are well simulated by the kinetic model. DFT studies\ud (ωB97X-D/SRSC) support coordination of CX·A to the groundstate Cu trimer and its rapid conversion to E.

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).

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.

Methods for the batch scale up of DABAL-Me3 promoted direct ester to amide synthesis have been demonstrated at 10–100 g scales using a tert-amide model compound. Procedures for 20 g scale couplings in standard laboratory glassware and up to 0.1 kg in industry-standard jacketed glass reactors in near quantitative yields are given. A derivative of the anticancer agent Imatinib (Gleevec) has been synthesized on a 26 g scale (98% yield, >98% purity) establishing DABAL-Me3 as a potential alternative for the synthesis of amides in API scale preparations. Continuous flow methodology provides a method for larger scales (productivities of >50 g h–1). In addition, nitriles were coupled to primary amines and hydrazines with DABAL-Me3, resulting in the clean formation of free amidines (16 examples) and amidrazones.

A series of dual CCR3/H1 antagonists based on a bispiperidine scaffold were discovered. Introduction of an acidic group overcame hERG liability. Bioavailability was optimised by modulation of physico-chemical properties and physical form to deliver a compound suitable for clinical evaluation.

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.