Novel ROCK inhibitors for the treatment of pulmonary arterial hypertension

A novel class of selective inhibitors of ROCK1 and ROCK2 has been identified by structural based drug design. PK/PD experiments using a set of highly selective Rho kinase inhibitors suggest that systemic Rho kinase inhibition is linked to a reversible reduction in lymphocyte counts. These results le...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2014-10, Vol.24 (20), p.4812-4817
Hauptverfasser:	Shaw, Duncan, Hollingworth, Greg, Soldermann, Nicolas, Sprague, Elizabeth, Schuler, Walter, Vangrevelinghe, Eric, Duggan, Nicholas, Thomas, Matthew, Kosaka, Takatoshi, Waters, Nigel, van Eis, Maurice J.
Format:	Artikel
Sprache:	eng
Schlagworte:	60 APPLIED LIFE SCIENCES Animals BASIC BIOLOGICAL SCIENCES Crystallography, X-Ray Disease Models, Animal Dose-Response Relationship, Drug Humans Hypertension, Pulmonary - drug therapy Hypertension, Pulmonary - enzymology Hypertension, Pulmonary - metabolism Inhibitors Intra-tracheal dosing Lymphocyte depletion Mice Mice, Inbred BALB C Models, Molecular Molecular Structure Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pulmonary arterial hypertension Rats Rats, Inbred Lew Rho kinase rho-Associated Kinases - antagonists & inhibitors rho-Associated Kinases - metabolism Structure-Activity Relationship
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Zusammenfassung:	A novel class of selective inhibitors of ROCK1 and ROCK2 has been identified by structural based drug design. PK/PD experiments using a set of highly selective Rho kinase inhibitors suggest that systemic Rho kinase inhibition is linked to a reversible reduction in lymphocyte counts. These results led to the consideration of topical delivery of these molecules, and to the identification of a lead molecule 7 which shows promising PK and PD in a murine model of pulmonary hypertension after intra-tracheal dosing.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2014.09.002