Herein, we present a synthetic compound library compris-ing of 28 anilino and benzylamino monosquarate-amide derivatives. Members of this library were designed as bioisosteric replacements for groups such as the ubiquitous carboxylic acid moiety. Further to their synthesis, we have shown the potential of these chemical building blocks for the generation of additional novel compounds. This work forms part of our efforts aimed at the assembly of 96-well plates loaded with bioisosteric analogues that may be used to enrich drug discovery programs. The research presented in this work focuses on the chemistry of 3,4-dihydroxycyclobut-3-ene-1,2-dione, a known carboxylic acid bioisostere.

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.

The Cover Feature shows new chiral tetrahydroquinoline carboxylates attained by asymmetric copper-catalyzed 1,4-addition of AlR3 “floating” above the countryside of Camerino, where the 12th International School of Organometallic Chemistry was held. More information can be found in the Full Paper by S. Woodward et al.

Under CuBr·SMe2/PPh3 catalysis (5/10 mol‐%) RMgCl (R = Me, Et, nPr, CH=CH2, nBu, iBu, nC5H11, cC6H11, Bn, CH2Bn, nC11H23) readily (–78 °C) undergo 1,4‐addition to Cbz or Boc protected quinolin‐4(1H)‐ones to provide 2‐alkyl‐2,3‐dihydroquinolin‐4(1H)‐ones (14 examples, 54–99 % yield). Asymmetric versions require AlEt3 to Boc‐protected ethyl 6‐substituted 4(1H)‐quinolone‐3‐carboxylates (6‐R group = all halogens, n/i/t‐alkyls, CF3) and provide 61–91 % yield, 30–86 % ee; any halogen, Me, or CF3 provide the highest stereoselectivities (76–86 % ee). Additions of AlMe3 or Al(nC8H17)3 provide ≈ 45 and ≈ 75 % ee on addition to the parent (6‐R = H). Ligand (S)‐(BINOL)P–N(CHPh2)(cC6H11) provides the highest ee values engendering addition to the Si face of the 4(1H)‐quinolone‐3‐carboxylate. Allylation and deprotection of a representative 1,4‐addition product example confirm the facial selectivity (X‐ray crystallography).

ReactIR studies of mixtures of AlEt3 (A) and cyclohex-2-en-1-one (CX) in Et2O indicate immediate formation of the Lewis acid-base complex CX center dot A at-40 degrees C (K = 12.0 M-1, Delta G(react) degrees=-1.1 kcal mol(-1)). Copper(I) catalysts, derived from precatalytic Cu(OAc)(2) (up to 5 mol %) and (R,S,S)-P(binaphtholate){N(CHMePh)(2)} (Feringa's ligand (L), up to 5 mol %) convert CX center dot A (0.04-0.3 M) into its 1,4-addition product enolate (E) within 2000 s at-40 C. Kinetic studies (ReactIR and chiral GC) of CX.A, CX, and (R)-3-ethylcyclohexanone (P, the H+ quenching product of enolate E) show that the true catalyst is formed in the first 300 s and this subsequently provides P in 82% ee. This true catalyst converts CX center dot A to E with the rate law [Cu](1.5)[L](0.66)[CX center dot A](1) when [L]/[Cu] <= 3.5. Above this ligand ratio inhibition by added ligand with order [L]-(2.5) is observed. A rate-determining step (rds) of Cu3L2(CX center dot A)(2) stoichiometry is shown to be most consistent with the rate law. The presence of the enolate in the active catalyst best accounts for the reaction's induction period and molecularity as [E] E [CX center dot A]. Catalysis proceeds through a "shuttling mechanism" between two C-2 symmetry related ground state intermediates. Each turnover consumes 1 equiv of CX center dot A, expels one molecule of E, and forms the new Cu-Et bond needed for the next cycle. The observed ligand (L) inhibition and a nonlinear ligand L ee effect on the ee of P are well simulated by the kinetic model. DFT studies (wB97X-D/SRSC) support coordination of CX center dot A to the groundstate Cu trimer and its rapid conversion to E.

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.

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.