Discovery of Riociguat (BAY 63-2521): A Potent, Oral Stimulator of Soluble Guanylate Cyclase for the Treatment of Pulmonary Hypertension

被引：151

作者：

Mittendorf, Joachim ^{[1
]}

Weigand, Stefan ^{[1
]}

Alonso-Alija, Cristina ^{[1
]}

Bischoff, Erwin ^{[2
]}

Feurer, Achim ^{[1
]}

Gerisch, Michael ^{[3
]}

Kern, Armin ^{[3
]}

Knorr, Andreas ^{[2
]}

Lang, Dieter ^{[3
]}

Muenter, Klaus ^{[2
]}

Radtke, Martin ^{[3
]}

Schirok, Hartmut ^{[1
]}

Schlemmer, Karl-Heinz ^{[3
]}

Stahl, Elke ^{[3
]}

Straub, Alexander ^{[1
]}

Wunder, Frank ^{[2
]}

Stasch, Johannes-Peter ^{[2
]}

机构：

[1] Bayer Schering Pharma AG, Med Chem Wuppertal, D-42096 Wuppertal, Germany

[2] Bayer Schering Pharma AG, Cardiovasc Res, D-42096 Wuppertal, Germany

[3] Bayer Schering Pharma AG, DMPK, D-42096 Wuppertal, Germany

来源：

CHEMMEDCHEM | 2009年 / 4卷 / 05期

关键词：

BAY; 63-2521; pulmonary hypertension; riociguat; sGC stimulation; vasorelaxation; NO-INDEPENDENT STIMULATORS; NITRIC-OXIDE; FUNCTIONAL-CHARACTERIZATION; CONVENIENT SYNTHESIS; YC-1; ACTIVATION; BAY-41-8543; DERIVATIVES; GENERATION; SILDENAFIL;

D O I：

10.1002/cmdc.200900014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Soluble 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 cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treatment of pulmonary hypertension (PH), a disabling disease associated with a poor prognosis. Previous sGC stimulators such as the pyrazolopyridines BAY 41-2272 and BAY 41-8543 demonstrated beneficial effects in experimental models of PH, but were associated with unfavorable drug metabolism and pharmacokinetic (DMPK) properties. Herein we disclose an extended SAR exploration of this compound class to address these issues. Our efforts led to the identification of the potent sGC stimulator riociguat, which exhibits an improved DMPK profile and exerts strong effects on pulmonary hemodynamics and exercise capacity in patients with PH. Riociguat is currently being investigated in phase III clinical trails for the oral treatment of PH.

引用

页码：853 / 865

页数：13

共 65 条

[1]

ALONSOALIJA C, 2003, Patent No. 03095451

[2] Experiments on the synthesis of purine nucleosides Part II A new and convenient synthesis of adenine [J].

Baddiley, J ;

Lythgoe, B ;

Todd, AR .

JOURNAL OF THE CHEMICAL SOCIETY, 1943, :386-387

[3] Nitric oxide-independent stimulation of soluble guanylate cyclase with BAY 41-2272 in cardiovascular disease [J].

Boerrigter, Guido ;

Burnett, John C., Jr. .

CARDIOVASCULAR DRUG REVIEWS, 2007, 25 (01) :30-45

[4]

Borsche W, 1934, LIEBIGS ANN CHEM, V512, P97

[5]

CARNEY RWJ, 1973, ORG PREP P, V5, P25

[6] A SYNTHESIS OF ADENINE - THE INCORPORATION OF ISOTOPES OF NITROGEN AND CARBON [J].

CAVALIERI, LF ;

TINKER, JF ;

BENDICH, A .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1949, 71 (02) :533-536

[7] Nitric oxide-dependent allosteric inhibitory role of a second nucleotide binding site in soluble guanylyl cyclase [J].

Chang, FJ ;

Lemme, S ;

Sun, Q ;

Sunahara, RK ;

Beuve, A .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (12) :11513-11519

[8] Efficient Pd-catalyzed amination of heteroaryl halides [J].

Charles, MD ;

Schultz, P ;

Buchwald, SL .

ORGANIC LETTERS, 2005, 7 (18) :3965-3968

[9] Efficacy and optimal dose of sildenafil in primary pulmonary hypertension [J].

Chockalingam, A ;

Gnanavelu, G ;

Venkatesan, S ;

Elangovan, S ;

Jagannathan, V ;

Subramaniam, T ;

Alagesan, R ;

Dorairajan, S .

INTERNATIONAL JOURNAL OF CARDIOLOGY, 2005, 99 (01) :91-95

[10] AN EFFICIENT CHEMOSELECTIVE SYNTHESIS OF NITRILES FROM PRIMARY AMIDES [J].

CLAREMON, DA ;

PHILLIPS, BT .

TETRAHEDRON LETTERS, 1988, 29 (18) :2155-2158

← 1 2 3 4 5 6 7 →