Novel 5-HT7 antagonists for the treatment of pruritus
Ended Project Grant Awarded Last action
- Award ID
- R43AR081768
- Recipient
-
Praeventix LLC UEI NLSMGTKWQR16
- Awarding agency
-
National Insititue of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $547,696
Award facts
- Assistance listing
- 93.846 Arthritis, Musculoskeletal and Skin Diseases Research
- Completion date
- Originally
- Place of performance
- Exton, PA 19341, USA
Award details come from USAspending.gov.
Description
- Abstract
- (abstract) evidence supporting serotonin (5-HT) as a contributing factor to the severity of pruritus has been widely reported. Elevated levels of 5-HT have been reported in patients with atopic dermatitis and chronic eczema, thus supporting 5-HT as a contributing factor. Additionally, 5-HT invokes dose-dependent scratching when administered via intradermal injection in rodents. Studies have demonstrated that 5-HT induces scratching sensations by activating a subset of receptors. Substantial evidence supports a role of peripheral 5-HT7 receptors in chronic itch via opening of the TRPA1 channel. Opening of the TRPA1 channel is reported to be required for the manifestation of chronic pruritus. 5-HT7 is CO-expressed with TRPA1 in a subset of primary afferent sensory neurons that innervate the skin. When 5-HT7 was activated with either 5-HT or a highly selective 5-HT7 agonist (LP-44) IT triggers neuronal excitation via calcium flux thru the TRPA1 channel in a cyclic AMP dependent matter. The involvement of 5-HT7 in pruritus was supported in vivo as intradermal administration of LP-44 into the cheek of mice evoked significant scratching behavior that was attenuated via pharmacological blockade with a selective 5-HT7 antagonist (SB-269970). 5-HT and LP-44 induced scratching was also attenuated in either 5-HT7 or TRPA1 knock-out mice. Additionally, 5-HT7 and TRPA1 knock-out mice displayed reduced scratching and skin lesion severity in an atopic dermatitis model (MC903 induced) where 5-HT levels were significantly increased at the affected site. This data suggests that a 5-HT7 antagonist could be useful for the treatment of pruritus. We have chosen 6 highly potent, selective 5-HT7 antagonists that display peripherally restricted pharmacokinetic (PK), good dermal penetration/permeability and safe preliminary admet profiles. We hypothesize that our novel 5-HT7 antagonists will attenuate scratching in murine models of pruritus (MC903) and provide a novel mechanism for treating pruritus. We will pursue a multipronged approach focused on identifying novel lead compounds suitable for advanced in vivo efficacy studies.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$3,392 | |
| Amendment | $0 | |
| Amendment | $275,544 | |
| Original award | $275,544 |
Quick answers
Who received award R43AR081768?
R43AR081768 was awarded to Praeventix LLC by National Insititue of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) on July 1, 2022.
How much is award R43AR081768 worth?
$547,696 has been obligated on R43AR081768.
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