Himbacine derivatives

In the initial phase of lead generation, the racemic himbacine derivative 2 was resolved using chiral HPLC. The enantiomer (+)-2a bearing absolute chirahty opposite to that of himbacine (e f-himbacine) was found to have 10-fold greater affinity toward PAR-1 in the binding assay than the enantiomer with natural absolute chirahty, (—)-2b. The absolute chirality was confirmed by enantiospe-cific synthesis starting from (/ )-3-butyne-2-ol (Scheme 19.1) [7]. 

Himbacine-derived Thrombin Receptor Antagonists s61 19.6.2.4 Generation of Aryl Himbacine Leads... 

Table 19.3 Summary of in vitro and pharmacokinetic data for representative aryl himbacine derivatives.

The discovery of nor-seco himbacine derivatives originated from the tetrahydro-thiopyranyl derivative 56. Raney nickel reduction of 56 gave the ring-opened product 57 (nor-seco himbacine ring system) that showed modest PAR-1 inhibition in the binding assay. Subsequently, the SAR of this lead series was thoroughly explored [10]. 

Doller, D Chackalamannil, S., Czamiecki, M McQuade, R and Ruperto, V. (1999) Design, synthesis, and structure—activity relationship studies of himbacine derived muscarinic receptor antagonists. Bioorganic and Medicinal Chemistry Letters, 9, 901-906. 

Clasby, M.C., Chackalamannil, S., Czamiecki, M., Doller, D. et al (2007) Himbacine derived thrombin recq>tor antagonists discovery of a new tricyclic... 

Himbacine derived thrombin receptor (PAR-1) antagonists structure-activity relationship of the lactone ring. Bioorganic and Medicinal Chemistry Letters, 16, 4969-4972. 

Chelliah MV, Eagen K, Guo Z, et al. Himbacine-derived thrombin receptor antagonists Cy-spirocyclic analogues ofvorapaxar. ylCS Med Chem Lett. 2014 5 561-565. 

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