BEGIN:VCALENDAR
VERSION:2.0
PRODID:-//Memento EPFL//
BEGIN:VEVENT
SUMMARY:Discovery of Riociguat: A Potent\, Oral Stimulator of Soluble Guan
 ylate Cyclase for the Treatment of Pulmonary Hypertension
DTSTART:20140430T171500
DTEND:20140430T181500
DTSTAMP:20260407T110400Z
UID:cb5c0573354447c2f1e5530bc368b363ef2419d61b1b4570abca7020
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. Joachim Mittendorf\, Director of Medicinal Chemistry\, B
 ayer Healthcare\, Germany\nSoluble guanylate cyclase (sGC) is a key signal
 -transduction enzyme activated by nitric oxide (NO). Impairments of the NO
 -sGC-signaling pathway have been implicated in the pathogenesis of various
  cardiovascular and other diseases. Direct stimulation of sGC therefore re
 presents a promising therapeutic strategy particularly for the treatment o
 f pulmonary hypertension (PH)\, a devastating disease where a markedly imp
 aired bioactivity of NO contributes to excessive pulmonary vasoconstrictio
 n.[1]\nDirect NO-independent sGC stimulation was first demonstrated in 199
 4 when Ko and colleagues reported cGMP-stimulating properties for benzylin
 dazole YC-1. Our initial chemical optimization program based on YC-1 as a 
 lead structure resulted in the identification of sGC stimulators such as p
 yrazolopyridine BAY 41-2272 with approximately 2-3 orders of magnitude hig
 her potency.\nBAY 41-2272 demonstrated beneficial effects in experimental 
 models of PH\, but was associated with unfavorable drug metabolism and pha
 rmacokinetic properties. These issues were addressed in an extended explor
 ation of the structure-activity-relationships[2] and led to the identifica
 tion of the potent sGC stimulator Riociguat\, which exhibits an improved D
 MPK profile and exerts strong effects on pulmonary hemodynamics and exerci
 se capacity in patients with PH. Based on robust efficacy in phase III cli
 nical studies Riociguat was recently appoved in Canada and the U.S. for th
 e treatment of two life-threatening forms of pulmonary hypertension.\n[1]
   Follmann M.\; Griebenow N.\; Hahn M. G.\; Hartung J.\; Mais F.-J.\; Mit
 tendorf J.\; Schaefer M.\; Schirok H. Stasch J.-P.\, Stoll F.\; Straub A. 
 Angew. Chem. Int. Ed. 2013\, 52\, 9442-9462: The Chemistry and Biology of 
 Soluble Guanylate Cyclase Stimulators and Activators.\n[2] Mittendorf\, J.
 \; Weigand S.\; Alonso-Alija C.\; Bischoff E.\; Feurer A.\; Gerisch M.\; K
 ern A.\; Knorr A.\; Lang D.\; Muenter K.\; Radtke M.\; Schirok H.\; Schlem
 mer K.-H.\; Stahl\, E.\; Straub A.\; Wunder F.\; Stasch J.-P. ChemMedChem 
 2009\, 4\, 853-865.
LOCATION:BCH 2218 https://plan.epfl.ch/?room==BCH%202218
STATUS:CONFIRMED
END:VEVENT
END:VCALENDAR