| Autor: |
McAtee JJ; Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA. jeff.j.mcatee@gsk.com, Dodson JW, Dowdell SE, Girard GR, Goodman KB, Hilfiker MA, Sehon CA, Sha D, Wang GZ, Wang N, Viet AQ, Zhang D, Aiyar NV, Behm DJ, Carballo LH, Evans CA, Fries HE, Nagilla R, Roethke TJ, Xu X, Yuan CC, Douglas SA, Neeb MJ |
| Jazyk: |
angličtina |
| Zdroj: |
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2008 Jun 15; Vol. 18 (12), pp. 3500-3. Date of Electronic Publication: 2008 May 10. |
| DOI: |
10.1016/j.bmcl.2008.05.027 |
| Abstrakt: |
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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