Sulfonamidolactam inhibitors of coagulation factor Xa.

As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors, the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally diverse chemotype that was further optimized to incorporate neutral or weakly basic aryl and heteroaryl P1 groups while maintaining good potency versus Factor Xa. Substitution at the sulfonamide nitrogen provided further improvements in potency and as did introduction of alternate P4 moieties.

SAR and factor IXa crystal structure of a dual inhibitor of factors IXa and Xa.

Modifications to the P4 moiety and pyrazole C3 substituent of factor Xa inhibitor SN-429 provided several new compounds, which are 5-10nM inhibitors of factor IXa. An X-ray crystal structure of one example complexed to factor IXa shows that these compounds adopt a similar binding mode to that previously observed with pyrazole inhibitors in the factor Xa active site both with regard to how the inhibitor binds and the position of Tyr99.

Synthesis and Biological Activity of 25-Methoxy-, 25-Fluoro-, and 25-Azabrassinolide and 25-Fluorocastasterone: Surprising Effects of Heteroatom Substituents at C-25.

The CuCN-catalyzed addition of 2-propenylmagnesium bromide to (threo-2R,3S,5alpha,22R,23R,24S)-23,24-epoxy-6,6-(ethylenedioxy)-2,3-(isopropylidenedioxy)-26,27-dinorcholestan-22-ol (11a) afforded the corresponding Delta(25)-22,23-diol 12. This was converted into 25-methoxybrassinolide (7) by protection as the 22,23-acetonide 13, oxymercuration in methanol, Baeyer-Villiger oxidation, and deprotection. Similarly, the addition of pyridinium poly(hydrogen fluoride) to 13 and deprotection afforded 25-fluorocastasterone (8), which was converted into 25-fluorobrassinolide (9) by Baeyer-Villiger oxidation. Treatment of threo-epoxide 11a with Me(2)NMgBr, followed by Baeyer-Villiger oxidation of the corresponding tetraacetate and saponification, provided 25-azabrassinolide (10). Epoxide 11a is therefore a versatile intermediate for the synthesis of side-chain analogues of brassinolide (1). 25-Methoxybrassinolide (7) displayed strong activity in the rice leaf lamina inclination bioassay, which was significantly enhanced by the simultaneous application of an auxin, indole-3-acetic acid (IAA). Thus, the presence of a 25-methoxy substituent, like that of the previously reported 25-hydroxy group in the 24-epibrassinolide series, yields a molecule with potent biological activity. On the other hand, 8-10 showed no bioactivity with or without IAA. This suggests that either the 25-fluoro and 25-aza substituents interfere with binding to a putative brassinosteroid receptor or that they prevent the in vivo enzymatic oxidation at C-25 that is required for bioactivity.