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Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).

Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).

Ro 31-8959 (1), a potent and selective inhibitor of HIV proteinase, is currently in phase III clinical trials. Six approaches for the large-scale synthesis of this compound have been studied. All routes employ an initial disconnection to an electrophilic L-phenylalanine homologue equivalent 13 and the decahydroisoquinoline derivative 5. They differ in adopting either an epoxide, a cyclic sulfate, or an aldehyde as the electrophilic entity and develop chirality from L-phenylalanine, dimethyl D-tartrate, or a Sharpless epoxidation. The preferred route starts from N-phthaloyl-L-phenylalaninyl chloride and uses tris((trimethylsilyl)oxy)ethene to effect homologation to hydroxy ketone 30, which is elaborated in a five-step two-pot procedure to N-phthaloyl epoxide 33 and hence 1. Kilogram quantities of Ro 31-8959 have been prepared using this route

A mild and flexible method for the preparation of bisindolylmaleimides from the corresponding indoles and indole-3-acetimidate esters is described.

A mild and flexible method for the preparation of bisindolylmaleimides from the corresponding indoles and indole-3-acetimidate esters is described.

t-Butyl hydroxy{4-[(Z)-2-(methoxycarbonyl)vinylthio]-2-oxoazetidin-1-yl}acetate (19a) was transformed into t-butyl 2-endo-methoxycarbonylmethyl-3-thiacepham-4-exo-carboxylate (20a) by sequential reactions involving thionyl chloride, potassium thioacetate, and cyclohexylamine. Oxidation of compound (20a) with potassium permanganate gave the 1,1,3,3-tetraoxide (23a), the structure of which was established by X-ray crystallography. The exceptional acidity of the 2- and 4-hydrogen atoms of compound (23a) was revealed by their replacement with deuterium atoms in the presence of deuterium oxide and with methyl groups in the presence of diazomethane. Cleavage of the t-butyl ester function of the thiacepham tetraoxide (23a) was effected by trifluoroacetic acid but the resultant acid (23b) underwent a rapid decarboxylation in water to give 2-endo-methoxycarbonylmethyl-3-thiacepham 1,1,3,3-tetraoxide (26a).

Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered (e.g., 52: GR binding Ki 0.7 nM; GR reporter gene functional Ki 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.

A virtual screening approach comprising a 3-D similarity search based on known GR modulators was used to identify a novel series of non-steroidal glucocorticoid receptor (GR) antagonists. Optimization of the initial hit to provide potent compounds which exhibit good selectivity against other steroidal nuclear hormone receptors is described.

The 2-azadecalin ring system was evaluated as a scaffold for the preparation of glucocorticoid receptor (GR) antagonists. High affinity, selective GR antagonists were discovered based on a hypothetical binding mode related to the steroidal GR antagonist RU-43044. 2-Benzenesulfonyl substituted 8a-benzyl-hexahydro-2H-isoquinolin-6-ones exemplified by (R)-37 had low nanomolar affinity for GR with moderate functional activity (200 nM) in a reporter gene assay. These compounds were devoid of affinity for other steroidal receptors (ER, AR, MR, and PR). Analogues based on an alternative putative binding mode (CP-like) were found to be inactive.

t-Butyl hydroxy{4-[(Z)-2-(methoxycarbonyl)vinylthio]-2-oxoazetidin-1-yl}acetate (19a) was transformed into t-butyl 2-endo-methoxycarbonylmethyl-3-thiacepham-4-exo-carboxylate (20a) by sequential reactions involving thionyl chloride, potassium thioacetate, and cyclohexylamine. Oxidation of compound (20a) with potassium permanganate gave the 1,1,3,3-tetraoxide (23a), the structure of which was established by X-ray crystallography. The exceptional acidity of the 2- and 4-hydrogen atoms of compound (23a) was revealed by their replacement with deuterium atoms in the presence of deuterium oxide and with methyl groups in the presence of diazomethane. Cleavage of the t-butyl ester function of the thiacepham tetraoxide (23a) was effected by trifluoroacetic acid but the resultant acid (23b) underwent a rapid decarboxylation in water to give 2-endo-methoxycarbonylmethyl-3-thiacepham 1,1,3,3-tetraoxide (26a).

Representatives of the title compounds have been prepared from a benzyl-penicillin-derived intermediate.

1,5-Bond ruptures may follow, but do not accompany, 4,7-bond cleavages of penicillanate 1,1-dioxides.

Complexes of imidazoline-2(1,3H)-thione (ImT,L), have been prepared with Co(II) and Zn(II) salts. Stoichiometries of the complexes, ML2X2, for the halides and ML4X2 for the nitrates and perchlorates, have been established by chemical analysis. Thermal analysis has revealed the extent of hydration among the cobalt complexes. The solid complexes have been further characterised by means of magnetic susceptibility data, infrared and visible spectral measurements. The soluble complexes have been studied by means of electrolytic conductance measurements and their visible spectra have also been recorded. Ligand field parameters have been determined and probable structures assigned. The ligand coordinated by means of its exocyclic sulphur atom and one of its ring nitrogen atoms in the solid complexes. For the soluble complexes coordination involves the sulphur atom only.

A procedure has been developed for the high-yield coupling of chiral acetals 1 with allyltrimethylsilane (2, R′=H) as well as with methallyltrimethylsilane (2,R′=ME) to afford the hydroxy ethers 3 in which the new chiral center is formed highly enantioselectively. Homoallylic alcohols 4 of high ee are produced by removal of the chiral auxiliary.

t-Butyl hydroxy-(2-iodomethyl-4-oxoazetidin-1-yl)acetate (10a), as a 1 : 1 mixture of diastereoisomers, was transformed, by sequential reactions involving thionyl chloride–2,6-lutidine and hydrogen sulphide–triethylamine, into a 1 : 1.7 mixture of t-butyl isopenam-3-exo-carboxylate (3b) and its endo-diasterepisomer (12a). Using a similar reaction sequence, p-nitrobenzyl hydroxy-(2-iodomethyl-4-oxoazetidin-1-yl)acetate (10b), as a 1 : 1 mixture of diastereoisomers, was converted into a 1 : 1.5 mixture of p-nitrobenzyl isopenam-3-exo-carboxylate (3d) and its endo-diastereoisomer (12b). In the presence of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), the endo-compounds (12a) and (12b) underwent epimerisations to the exo-isomers (3b) and (3d).Oxidation of the isopenams (3b), (3d), and (12a) with potassium permanganate gave the corresponding isopenam 2,2-dioxides, i.e.(4b), (4c), and (22). Epimerisation of the endo-compound (22) to its exo-diastereoisomer (4b) was effected by DBN.Hydrogenolyses of the p-nitrobenzyl esters (3d) and (4c), over palladium and in the presence of sodium hydrogen carbonate, gave the sodium salts of isopenam-3-exo-carboxylic acid and 3-exo-carboxyisopenam 2,2-dioxide, i.e.(3a) and (4a), respectively. Although stable in aqueous solution, the sodium salts (3a) and (4a) were inactive as antibacterial agents. The sodium salt (4a), unlike its analogue sulbactam sodium salt (21a), was ineffective as a β-lactamase inhibitor.When treated with trifluoroacetic acid, the isopenams (3b) and (12a) were converted respectively, into trans-(2-t-butoxycarbpnyl-3-trifluoroacetylthiazolidin-4-yl)acetic acid (13b) and its cis-diastereoisomer (14b). Under similar conditions, the isopenam dioxides (4b) and (22) afforded trans-2-t-butoxycarbonyl-4-methonycarbonylmethyl-3-trifluoroacetylthiazolidine 1,1-dioxide (13e) and its cis-diastereoisomer (14d). Trifluoroacetolysis of sulbactam benzyl ester (21b) gave (2R,4S)-4-benzyloxy-carbonyl-2-methoxycarbonylmethyl-5,5-dimethyl-3-trifluoroacetylthiazolidine 1,1-dioxide (26b).The aforecited results suggest that 3,4-bond ruptures do not accompany β-lactam cleavages of compounds (3b), (4b), (12a), and (22) and that a 1,5-bond breakage is not associated with rupture of the β-lactam linkage of sulbactam benzyl ester (21b). The failure to observe such fragmentation processes is interpreted in terms of unfavourable stereoelectronic factors. N-Unsubstituted thiazolidine 1,1-dioxides, species with hitherto have never been isolated or detected, are implicated as intermediates in the trifluoroacetolyses of compounds (4b), (21b), and (22).

β-Lactam-cleavage reactions of the 3-exo- and 3-endo-isomers of t-butyl isopenam-3-carboxylate, i.e.(2a) and (3a), and of 3-t-butoxycarbonylisopenam 2,2-dioxide, i.e.(2b) and (3b), induced by trifluoroacetic acid, are not accompanied or followed by 2,3-bond ruptures.

Representatives of the title compounds have been prepared from 4-(cis-β-methoxycarbonylvinylthio)azetidin-2-one.

Die β-Lactame (I) werden durch Trifluoressigsaure gespalten und mit Diazomethan zu den Estern (II) umgesetzt.

Representatives of the title compounds have been prepared from 4-(cis-β-methoxycarbonylvinylthio)azetidin-2-one.