A Highly Efficient Total Synthesis of (+)-Himbacine

Chackalamannil, Samuel; Davies, Robert J. O.; Asberom, Theodros; Doller, and Darío; Leone, Daria

doi:10.1021/ja962542f

Cited by 90 publications

(41 citation statements)

References 23 publications

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“…However, the complex structures of imperialine and himbacine have made SAR development challenging. By incorporating elements of himbacine total syntheses [Hart et al, 1995;Chackalamannil et al, 1996], several himbacine analogs were studied [Doller et al, 1999]. In addition, simplified derivatives of himbacine have been examined [Malaska et al, 1993[Malaska et al, , 1995, but neither of these approaches resulted in improvement over the M 2 selectivity of the natural product.…”

Section: Natural Product-based M 2 Antagonistsmentioning

confidence: 99%

Orally active and selective benzylidene ketal M₂ muscarinic receptor antagonists for the treatment of Alzheimer's disease

Boyle¹,

Lachowicz²

2002

Drug Development Research

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Numerous studies have implicated the cholinergic system as a target for Alzheimer's disease (AD) therapy. The currently marketed drugs for treatment of AD are acetylcholinesterase inhibitors, which increase levels of the neurotransmitter acetylcholine (ACh) by blocking its metabolic degradation. However, this mechanism results in a non-selective enhancement of cholinergic activity in peripheral organs as well as brain, which could lead to detrimental side effects. Cholinergic enhancement in brain can also be achieved by blocking presynaptic release-regulating autoreceptors. M 2 muscarinic receptor activation inhibits ACh release in brain regions that are critical for learning and memory processes. Thus, M 2 antagonists may prove beneficial for relief of cognitive deficits in AD. In this review, early discoveries of M 2 muscarinic antagonists based on dibenzodiazepinones, natural products, piperazines, and piperidines are described. More specifically, the development of a benzylidene ketal class of M 2 muscarinic antagonists is reviewed. Characterization and optimization of these agents have led to the identification of compounds with high M 2 receptor affinity and subtype selectivity. These M 2 antagonists also facilitate ACh release and enhance cognition in preclinical experimental paradigms. While clinical efficacy of these compounds has not been evaluated, M 2 antagonists represent a promising treatment for AD. Drug Dev. Res. 56:310-320, 2002.

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Section: Natural Product-based M 2 Antagonistsmentioning

confidence: 99%

Orally active and selective benzylidene ketal M₂ muscarinic receptor antagonists for the treatment of Alzheimer's disease

Boyle¹,

Lachowicz²

2002

Drug Development Research

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“…12,31,32 It is a potent antagonist of the PAR-1 receptor, blocking thrombin-mediated platelet activation without interfering with thrombin-mediated cleavage of fibrinogen. In particular, vorapaxar is a nonprotein small molecule with high affinity, and is an orally active, competitive inhibitor of PAR-1 12,31,32. After oral administration, this drug is absorbed rapidly with high bioavailability.…”

Section: Pharmacokinetics and Pharmacodynamics Of Vorapaxarmentioning

confidence: 99%

Unmet needs in the management of acute myocardial infarction: role of novel protease-activated receptor-1 antagonist vorapaxar

Cho

Rollini

Franchi

et al. 2014

VHRM

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Platelet activation with subsequent aggregation is a complex process leading to thrombus formation, which remains a key component for atherothrombotic manifestations, in particular myocardial infarction. Therefore, antiplatelet therapies are pivotal for the treatment of these patients. Current oral antiplatelet therapies used for secondary prevention of ischemic recurrences include aspirin and adenosine diphosphate P2Y12 platelet-receptor antagonists. However, despite these therapies, patients who have experienced a myocardial infarction remain at risk for ischemic recurrences. Therefore, more aggressive secondary prevention measures have been an area of research, including identifying additional targets modulating platelet-activation and -aggregation processes. Among these, thrombin-mediated platelet activation via protease-activated receptors (PARs) has been subject to extensive clinical investigation. Several PAR-1 receptor antagonists have been developed. However, vorapaxar is the only one that has completed large-scale clinical investigation. The present manuscript will provide an overview on the role of thrombin-mediated signaling, the impact of PAR-1 blockade with vorapaxar on ischemic and bleeding outcomes, and the potential role for vorapaxar in clinical practice.

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“…Vorapaxar is a synthetic tricyclic 3‐phenylpyridine analogue of himbacine, a natural product that has been modified as a crystalline salt for drug development and clinical use (Figure 3) [71, 72]. Vorapaxar is a nonprotein, small‐molecule, high‐affinity, orally active, competitive PAR‐1 inhibitor [71, 72].…”

Section: Vorapaxar (Sch530348)mentioning

confidence: 99%

Antiplatelet therapy: thrombin receptor antagonists

Tello‐Montoliu

Tomasello

Ueno

et al. 2011

Brit J Clinical Pharma

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Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. Multiple pathways contribute to platelet activation. Aspirin, an irreversible inhibitor of thromboxane A2 synthesis, in combination with clopidogrel, an inhibitor of P2Y12 adenosine diphosphate platelet receptors, represent the current standard-of-care of antiplatelet therapy for patients with acute coronary syndrome and for those undergoing percutaneous coronary intervention. Although these agents have demonstrated significant clinical benefit, the increased risk of bleeding and the recurrence of thrombotic events represent substantial limitations. Thrombin is one of the most important platelet activators. The inhibition of protease-activated receptor 1 showed a good safety profile in preclinical studies. In fact, phase II studies with vorapaxar (SCH530348) and atopaxar (E5555) showed no increase of bleeding events in addition to the current standard-of-care of antiplatelet therapy. Although the results of phase III trials for both drugs are awaited, this family is a promising new addition to the current clinical practice for patients with atherothrombotic disease, not only as an alternative, but also as additional therapy.

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A Highly Efficient Total Synthesis of (+)-Himbacine

Cited by 90 publications

References 23 publications

Orally active and selective benzylidene ketal M₂ muscarinic receptor antagonists for the treatment of Alzheimer's disease

Orally active and selective benzylidene ketal M₂ muscarinic receptor antagonists for the treatment of Alzheimer's disease

Unmet needs in the management of acute myocardial infarction: role of novel protease-activated receptor-1 antagonist vorapaxar

Antiplatelet therapy: thrombin receptor antagonists

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A Highly Efficient Total Synthesis of (+)-Himbacine

Cited by 90 publications

References 23 publications

Orally active and selective benzylidene ketal M2 muscarinic receptor antagonists for the treatment of Alzheimer's disease

Orally active and selective benzylidene ketal M2 muscarinic receptor antagonists for the treatment of Alzheimer's disease

Unmet needs in the management of acute myocardial infarction: role of novel protease-activated receptor-1 antagonist vorapaxar

Antiplatelet therapy: thrombin receptor antagonists

Contact Info

Product

Resources

About

Orally active and selective benzylidene ketal M₂ muscarinic receptor antagonists for the treatment of Alzheimer's disease

Orally active and selective benzylidene ketal M₂ muscarinic receptor antagonists for the treatment of Alzheimer's disease