title: Novel ROCK inhibitors for the treatment of pulmonary arterial hypertension.
abstract: 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.
authors.affiliation: Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom. Electronic address: duncan.shaw@novartis.com.
authors.forename: Duncan
authors.initials: D
authors.lastname: Shaw
authors.affiliation: Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Greg
authors.initials: G
authors.lastname: Hollingworth
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1 Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Soldermann
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sprague
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1 Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Schuler
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1 Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Vangrevelinghe
authors.affiliation: Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Duggan
authors.affiliation: Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kosaka
authors.affiliation: Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Waters
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1 Novartis Campus, 4056 Basel, Switzerland. Electronic address: maurice.van_eis@novartis.com.
authors.forename: Maurice J
authors.initials: MJ
authors.lastname: van Eis
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases
keywords: Inhibitors; Intra-tracheal dosing; Lymphocyte depletion; Pulmonary arterial hypertension; Rho kinase