Abstract
β-Blockers reducemortality andimprove symptoms inpeople withheartdisease;however, current clinically available β-blockers have poor selectivity for the cardiac β1-adrenoceptor (AR) over the lung β2-AR. Unwanted β2-blockade risks causing life-threatening bronchospasm and reduced efficacy of β2-agonist emergency rescue therapy. Thus, current life-prolonging β-blockers are contraindicated in patients with both heart disease and asthma. Here, we describeNDD-713 and -825, novel highly β1-selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays that use human receptors expressed inChinesehamster ovary cellsdemonstrate that NDD-713 and-825 have nanomolar β1-AR affinity >500-fold β1-AR vs. β2-AR selectivity and no agonism. Studies in conscious rats demonstrate that these antagonists are orally bioavailable and cause pronounced β1-mediated reduction of heart rate while showing no effect on β2-mediated hindquarters vasodilatation. These compounds also have good disposition properties and show no adverse toxicologic effects. They potentially offer a truly cardioselective β-blocker therapy for the large number of patientswith heart and respiratory or peripheral vascular comorbidities.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3150-3166 |
| Number of pages | 17 |
| Journal | FASEB Journal |
| Volume | 31 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2017 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics
Cite this
Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. / Baker, Jillian G.; Gardiner, Sheila M.; Woolard, Jeanette; Fromont, Christophe; Jadhav, Gopal; Mistry, Shailesh N.; Thompson, Kevin S.J.; Kellam, Barrie; Hill, Stephen J.; Fischer, Peter M.
In: FASEB Journal, Vol. 31, No. 7, 01.07.2017, p. 3150-3166.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease
AU - Baker, Jillian G.
AU - Gardiner, Sheila M.
AU - Woolard, Jeanette
AU - Fromont, Christophe
AU - Jadhav, Gopal
AU - Mistry, Shailesh N.
AU - Thompson, Kevin S.J.
AU - Kellam, Barrie
AU - Hill, Stephen J.
AU - Fischer, Peter M.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - β-Blockers reducemortality andimprove symptoms inpeople withheartdisease;however, current clinically available β-blockers have poor selectivity for the cardiac β1-adrenoceptor (AR) over the lung β2-AR. Unwanted β2-blockade risks causing life-threatening bronchospasm and reduced efficacy of β2-agonist emergency rescue therapy. Thus, current life-prolonging β-blockers are contraindicated in patients with both heart disease and asthma. Here, we describeNDD-713 and -825, novel highly β1-selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays that use human receptors expressed inChinesehamster ovary cellsdemonstrate that NDD-713 and-825 have nanomolar β1-AR affinity >500-fold β1-AR vs. β2-AR selectivity and no agonism. Studies in conscious rats demonstrate that these antagonists are orally bioavailable and cause pronounced β1-mediated reduction of heart rate while showing no effect on β2-mediated hindquarters vasodilatation. These compounds also have good disposition properties and show no adverse toxicologic effects. They potentially offer a truly cardioselective β-blocker therapy for the large number of patientswith heart and respiratory or peripheral vascular comorbidities.
AB - β-Blockers reducemortality andimprove symptoms inpeople withheartdisease;however, current clinically available β-blockers have poor selectivity for the cardiac β1-adrenoceptor (AR) over the lung β2-AR. Unwanted β2-blockade risks causing life-threatening bronchospasm and reduced efficacy of β2-agonist emergency rescue therapy. Thus, current life-prolonging β-blockers are contraindicated in patients with both heart disease and asthma. Here, we describeNDD-713 and -825, novel highly β1-selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays that use human receptors expressed inChinesehamster ovary cellsdemonstrate that NDD-713 and-825 have nanomolar β1-AR affinity >500-fold β1-AR vs. β2-AR selectivity and no agonism. Studies in conscious rats demonstrate that these antagonists are orally bioavailable and cause pronounced β1-mediated reduction of heart rate while showing no effect on β2-mediated hindquarters vasodilatation. These compounds also have good disposition properties and show no adverse toxicologic effects. They potentially offer a truly cardioselective β-blocker therapy for the large number of patientswith heart and respiratory or peripheral vascular comorbidities.
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UR - http://www.scopus.com/inward/citedby.url?scp=85021685950&partnerID=8YFLogxK
U2 - 10.1096/fj.201601305R
DO - 10.1096/fj.201601305R
M3 - Article
VL - 31
SP - 3150
EP - 3166
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 7
ER -