Himbacine lead generation

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... 

The above narrative exemplifies a successful lead identification story, ensued by a successful lead optimization that led to the discovery of the FDA-approved drug vorapaxar. The original hit (2) was a racemic synthetic analog of himbacine, a natural product that has no thrombin receptor activity. Had we made this analog in the absolute chirality of himbacine, we would have missed the hit, since the thrombin receptor antagonist activity is exclusive to the unnatural e t-him-bacine series. The lead optimization efforts encountered several obstacles, as highlighted by the discontinuation of two recommended candidates. Within the project, we had to return several times to secondary lead generation and optimization in order to address the liabilities such as liver enzyme induction and sub-optimal mass balance that we encountered in the development candidates. 

Figure 19.4 The key step in the total synthesis of himbacine employed a highly diastereose-lective IMDA reaction [6]. A similar IMDA reaction was used to generate the tricyclic aldehyde 19 needed for optimization of the himbadne-derived PAR-1 lead [7],...

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