Delving into the Latest Updates on LEO-39652 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

LEO 39652

Target

PDE4

Action

inhibitors

Mechanism

PDE4 inhibitors(Phosphodieterase 4 inhibitors)

Therapeutic Areas

Immune System DiseasesCongenital DisordersSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

Dermatitis, AtopicMild Atopic DermatitisModerate Atopic Dermatitis

Originator Organization

LEO Pharma A/S

Active Organization-

Inactive Organization

Leo Pharma, Inc.

LEO Pharma A/S

License Organization-

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC23H23N3O5

InChIKeyLUUUHUYQTLUIDG-UHFFFAOYSA-N

CAS Registry1445656-91-6

Author: Knudsen, Nina Oe. ; Ollerstam, Anna ; Pettersson, Henrik ; Soerensen, Morten D. ; Larsen, Jens ; Eirefelt, Stefan ; Vifian, Thomas ; Hegardt, Pontus ; Eskilsson, Cecilia ; Larsen, Mogens ; Skak-Nielsen, Tine ; Soehoel, Anders ; Lambert, Maja ; Hansen, Lene M. ; Laursen, Steen ; Stilou, Tatiana G. ; Nielsen, Simon F.

We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.

01 Dec 2020·Pharmaceutical researchQ3 · MEDICINE

Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion and Skin Biopsies

Q3 · MEDICINE

Article

Author: Johansson, Fredrik ; Bertelsen, Malene ; Hummer, Joanna ; Birngruber, Thomas ; Lambert, Maja ; Sinner, Frank ; Basse, Line Hollesen ; Larsen, Jens ; Nielsen, Simon Feldbæk ; Eirefelt, Stefan

PURPOSE:

To investigate the difference in clinical efficacy in AD patients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants.

METHODS:

Clinical formulations were applied to intact or barrier disrupted human skin explants and both skin biopsy samples and dermal interstitial fluid was sampled for measuring drug concentration. Furthermore, cAMP levels were determined in the skin biopsies as a measure of target engagement.

RESULTS:

Elevated cAMP levels were observed with LEO 29102 while no evidence of target engagement was obtained with LEO 39652. In barrier impaired skin the dISF concentration of LEO 29102 was 2100 nM while only 33 nM for LEO 39652. For both compounds the concentrations measured in skin punch biopsies were 7-33-fold higher than the dISF concentrations.

CONCLUSIONS:

Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution.

100 Deals associated with LEO-39652

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Mild Atopic Dermatitis	Phase 1	Germany	Leo Pharma, Inc.	01 Jul 2014
Moderate Atopic Dermatitis	Phase 1	Germany	Leo Pharma, Inc.	01 Jul 2014
Dermatitis, Atopic	Phase 1	United Kingdom	Leo Pharma, Inc.	01 May 2013