Heterotricyclic Himbacine Analogs as Potent, Orally Active Thrombin Receptor (Protease Activated Receptor-1) Antagonists

Abstract

Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.

Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention?

“…PAR 1 antagonists based on the core structure of the tetracyclic piperidine alkaloid, himbacine, from Australian magnolia trees have also recently been developed ( Chackalamannil, 2006 ). The most potent PAR 1 antagonist in this series demonstrates excellent affinity ( K i of 4.3 nM), good oral bioavailability (∼62%) and blocks platelet aggregation in the cynomolgus monkey model up to 70% at a dose of 3 mg kg −1 ( Chelliah et al , 2007 ).…”

Natural products to drugs: natural product-derived compounds in clinical trials

“…370 An extensive medicinal chemistry programme involving the synthesis of over 2000 analogues, including two discontinued early development candidates, was undertaken until the final orally bioavailable candidate, SCH 530348 120, was identified. [370][371][372][373][374] SCH 530348 120 is in Phase III trials for the secondary prevention of cardiovascular diseases such as atherosclerosis, ischemia, myocardial infarction and stroke.…”

Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine

“… Initially investigated for its potent antagonist effects for muscarine receptors, research was stymied by a lack of reliable availability of the compound. Therefore, access to himbacine, and subsequent analogs, was reliant on total synthesis. , Chackalamannil and co-workers used their scalable synthetic route to develop substituted pyridine derivatives of himbacine that showed increased binding to the protease-activated receptor-1 (PAR-1). , PAR-1 is a thrombin activated G-protein-coupled receptor involved in platelet activation, making it a valuable antiplatelet target for the treatment of cardiovascular disease. Subsequent derivatization of himbacine added an ethyl carbamate at the C-7 position of the tricyclic core, which further improved potency and oral availability .…”