Exploring the chiral space within the active site of α-thrombin with a constrained mimic of d -Phe-Pro-Arg — design, synthesis, inhibitory activity, and X-ray structure of an enzyme–inhibitor complex

Phenolic P2/P3 core motif as thrombin inhibitors—Design, synthesis, and X-ray co-crystal structure

“…5 Low to moderate nanomolar inhibition was observed, thus validating the initial design concept which focused on constrained and conformationally rigidified analogues of the natural substrate D D-Phe-Pro-Arg. We have also reported on related indolizidinones designed to target Factor VIIa.…”

Structure‐Based Organic Synthesis of Drug Prototypes: A Personal Odyssey

“…[157] Key steps in the synthesis of these indolizidinones were the stereocontrolled introduction of hydroxy and amino groups at tertiary carbon atoms via lactam enolate chemistry. [155][156][157][158] Synthetic approaches to indolizidinones and related bicyclic lactam carboxylic acids have been reported by us and various other research groups.…”

“…[133] However, its use was recently discontinued owing to some toxicity. [154] Extensive modeling studies in collaboration with scientists at AstraZeneca (Mçlndal, Sweden) led to the design and synthesis of constrained analogues of d-Phe-l-Pro-l-Arg, exemplified by the indolizidinone 88 (IC 50 = 18 nm against thrombin), [155] shown in Figure 19. A co-crystal structure with thrombin showed the expected interactions.…”

Synthetic and Natural Peptides as Antithrombotic Agents—A View on the Current Development

“…the oldest systematic data in the literature concerning the anticoagulant structures on the basis of amino acids and peptides date back to 1975 when Bajusz et al reported their work on the tripeptide sequence D-Phe-Arg-Pro-H (7). This sequence showed exceptionally hopeful in vivo results, which led to a number of investigations on its modifications (8,46). About 10 years later a synthesis and biological activity of a new tripeptide sequences tyr-ileArg and Phe-ile-Arg were described (71).…”