Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species

Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.

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3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as High Affinity, Selective, and Orally Bioavailable h5-HT2AReceptor Antagonists†

Journal of Medicinal Chemistry ◽

10.1021/jm0004998 ◽

2001 ◽

Vol 44 (10) ◽

pp. 1603-1614 ◽

Cited By ~ 85

Author(s):

Michael Rowley ◽

David J. Hallett ◽

Simon Goodacre ◽

Christopher Moyes ◽

James Crawforth ◽

...

Keyword(s):

High Affinity ◽

Orally Bioavailable

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Further Studies on the Mechanism for the Antithrombotic Effects of Naroparcil, an Orally Active Thioxyloside Compound

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614604 ◽

1999 ◽

Vol 81 (06) ◽

pp. 945-950 ◽

Cited By ~ 6

Author(s):

J. Theveniau ◽

D. Coup ◽

T. Grégoire ◽

M. Vaillot ◽

D. Dupouy ◽

...

Keyword(s):

Specific Activity ◽

Heparin Cofactor Ii ◽

Antithrombotic Activity ◽

Thrombin Inhibition ◽

High Affinity ◽

Antithrombotic Effects ◽

Orally Active ◽

The Relationship ◽

In Vitro Specific Activity

SummaryThe antithrombotic β-D-xyloside, naroparcil, has previously been shown to induce a dose-related increase of circulating glycosaminoglycans (GAGs) together with an antithrombin activity (anti-IIa) via heparin cofactor II (HCII) in the rabbit. In order to go further in the mechanisms, the relationship between the antithrombotic activity, the HCII-mediated anti-IIa activity and the plasma GAG content was investigated. We showed that the in vitro specific activity on the inhibition of thrombin by HCII of the plasma GAG extract from naroparcil-treated rabbits was increased by a factor of 60 when compared to controls. In addition, the fractionation of the plasma GAG extract by affinity chromatography on immobilized HCII led to a more potent material whereas the low-affinity fraction was shown to be inactive in thrombin inhibition by HCII.The qualitative analysis of GAGs showed the presence of the ΔDi-4S DS disaccharide, undetectable in control, which accounted for 22% in the unfractionated GAG extract and for 60% in the high affinity fraction. In vitro experiments using immuno-depleted plasma in antithrombin III (ATIII), HCII or both, indicated that the anti-IIa activity of the plasma GAG extract from naroparcil-treated rabbits was mainly due to HCII potentialisation. The unfractionated GAG extract and the high affinity fraction were shown to be antithrombotic in a Wessler-based model in the rat, giving ED80 values of 610 UA/kg and 56 UA/kg respectively whereas the low-affinity fraction was devoid of any antithrombotic activity. These results show that the antithrombotic activity of naroparcil is dependent on modification in the plasma GAG profile which inactivates thrombin via the HCII.

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Low-Affinity Material Does not Contribute to the Antithrombotic Activity of Orgaran (Org 10172) in Human Plasma

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642519 ◽

1994 ◽

Vol 71 (06) ◽

pp. 759-767 ◽

Cited By ~ 3

Author(s):

Adrian Zammit ◽

Joan Dawes

Keyword(s):

Human Plasma ◽

Apolipoprotein B ◽

Plasma Proteins ◽

Chondroitin Sulphate ◽

Heparan Sulphate ◽

Factor Xa ◽

Dermatan Sulphate ◽

Antithrombotic Activity ◽

High Affinity

SummaryOrgaran is a LMW heparinoid composed of heparan sulphate (83% wlw) of which 4-5% has high affinity for antithrombin, dermatan sulphate (12% w/w) and chondroitin sulphate (59 wlw). To examine the contribution of the low-affinity fraction to Orgaran’s antithrombotic activity we have quantitated the binding of plasma proteins to Orgaran and its component fractions in whole, hirudin-anticoagulated human plasma. Antithrombin, largely bound to the high-affinity fraction, and histidine-rich glycoprotein, interacting with low-affinity components, were the dominant proteins bound to Orgaran. Vitronectin, fibrinogen, fibronectin, heparin cofactor 11, and apolipoprotein B were also detected in small amounts. The ratio of bound antithrombin, histidine- rich glycoprotein and vitronectin to GAG was negatively correlated with the Orgaran concentration in plasma, implying that the efficacy of Orgaran may not be linearly related to dose. Binding of antithrombin to the high-affinity fraction was not decreased by other plasma proteins or affected by addition of low-affinity material. Moreover, the antithrombin and anti-factor Xa activities of the high-affinity material were unaltered by low-affinity GAGs. On the basis of our results we conclude that the low-affinity material does not contribute to the antithrombotic activity of Orgaran by binding non-anticoagulant plasma proteins and releasing the high-affinity chains to interact with antithrombin and its target proteinases.

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