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    • The synthesis of compounds in which the ethyl linker has

    2024-03-16

    The synthesis of compounds in which the ethyl linker has been modified to the carbamate and urea derivatives , and is shown in . Thus the diamine was reacted with glycolic HS-173 to give the alcohol followed by Mitsunobu reaction with phthalimide to give . Deprotection with hydrazine gave the amine which was derivatised to the carbamate and ureas –. The alcohol was converted to the isomeric carbamate by reaction with the appropriate isocyanate. The oxygen and sulfur linked compounds , , and were prepared as shown in . The diamine was converted to the thiol with carbon disulfide and then methylated to give . Oxidation of with potassium permanganate gave the sulfone which was displaced with benzyl 2-hydroxyacetate to give . Debenzylation of followed by amide coupling gave the ether linked compounds –. For the sulfur linked compounds , and , thiol was alkylated with -butyl-2-bromoacetate to give which was deprotected with trifluoroacetic acid to give the acid . Amide coupling gave the thioether and oxidation of with potassium permanganate gave the sulfone Oxidation of with 3-chloroperbenzoic acid gave the sulfoxide diastereomers and (this reaction gives a pair of diastereomers because R is chiral with defined absolute stereochemistry). Compounds bearing the isomeric imidazo[4,5-]pyridine core were synthesized as shown in . Displacement of the bromide with the appropriate benzylamine gave which was reduced to the diamine with hydrogen and 10% Pd/C. The -oxide was reduced to the diamine with iron in acetic acid followed by reaction with succinic anhydride to give the acid . Amide coupling of using HBTU gave the target compounds –. summarises the effect of modifications to R and R in compound . Looking at the R group compound shows that removal of the 4-OMe substituent reduced biochemical potency whereas replacement with 4-fluoro or 4-methyl maintained activity. Introduction of the polar sulfone substituent significantly reduced potency suggesting that the 4-substituent in R is accessing a lipophilic pocket in the binding site. This is further supported by the 40 fold increase in potency observed when a chloro group was introduced at the 4-position ( vs ). Despite the improved biochemical potency for the activity seen in the plasma CRA assay was only modest. Substitution at the 2- and 3-positions of R (–) or chain extension to the phenyethyl group generally reduced potency. Saturation of the aromatic ring to give was tolerated but replacement with polar aromatic rings such as the pyridine markedly reduced potency. A major breakthrough in potency was achieved by introduction of a chiral methyl group on the benzylic carbon of R which restricted the conformation of the aromatic ring ( and ). The ()-isomer was found to be 38 fold more potent than the ()-isomer and the introduction of the ()-methyl group resulted in an 18 fold increase in potency compared to the unsubstituted benzyl derivative ( vs ). The separation in potency between the () and () isomers is further highlighted in compounds and . The ()-isomers and also now showed improved activity in the plasma CRA assay. Combining the two potency enhancing features from and into a single molecule gave which demonstrated single digit nanomolar potency in the biochemical assay. Further optimisation of the 4-position of R resulted compounds such as and which showed high potency in both the biochemical and plasma CRA assays. Due to the lipophilic nature of the ATX binding pocket the Log of the molecules also tended to increase as potency was optimised. We were able to address this drawback to some extent by introduction of the polar hydroxymethyl group shown in . The intrinsic clearance in mouse microsomes for , , , , and – was found to be high and the only compound with moderate intrinsic clearance was the hydroxymethyl derivative which has the lowest Log of the compounds tested. We then explored the linker portion of the molecule as shown in . The ether linked compound showed good potency but had high microsomal intrinsic clearance The urea linked compounds – showed a drop in potency particularly in the plasma CRA assay and the carbamates and and sulfone were also significantly less active. The thioether analogue was highly potent and, of the two corresponding sulfoxide diastereomers and , compound was more potent in the biochemical assay. The difference in potency observed between the thioether , the sulfone , and the sulfoxides and suggests that one of the oxygen atoms on the sulfur has an unfavourable interaction with the protein. Good potency was also achieved when the core scaffold was modified to the imidazo[4,5-]pyridine ring system (). Comparative in vitro potency data for the published ATX inhibitor PF-8380 is provided in the .