Pharmacophore-based search, synthesis, and biological evaluation of anthranilic amides as novel blockers of the Kv1.5 channel

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 11, 2004, Pages 2823-2827

  Peukert, Stefan ^a   Brendel, Joachim ^a   Pirard, Bernard ^a   Strübing, Carsten ^a   Kleemann, Heinz Werner ^a   Böhme, Thomas ^a   Hemmerle, Horst ^a,b  

^a SANOFI AVENTIS DEUTSCHLAND GMBH   (Germany)

^b ELI LILLY AND COMPANY   (United States)

Author keywords

Anthranilic amides; Atrial fibrillation; Kv1.5 blockers

Indexed keywords

AMIDE; ANTHRANILIC ACID DERIVATIVE; POTASSIUM CHANNEL BLOCKING AGENT;

ARTICLE; CHEMICAL REACTION; CONTROLLED STUDY; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; IC 50; NONHUMAN; PHARMACOPHORE; RAT; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; AMIDES; ANIMALS; ANTHRANILIC ACIDS; BIOLOGICAL AVAILABILITY; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; INHIBITORY CONCENTRATION 50; KV1.5 POTASSIUM CHANNEL; MODELS, MOLECULAR; POTASSIUM CHANNEL BLOCKERS; POTASSIUM CHANNELS, VOLTAGE-GATED; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 2342469473     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.03.057     Document Type: Article

References (15)

1. Pratt C.M., Moye L.A. Am. J. Cardiol. 65:1990;20B
2. Waldo A.L., Camm A.J., Deruyther H. Lancet. 348:1996;7
3. Tomaselli G. Heart Drug. 1:2001;183
4. Bril A. Curr. Opin. Pharmacol. 2:2002;154
5. Nishida A., Uemura H., Ogura T., Furusawa H., Yabana H., Nakaya H. Jpn. J. Pharmacol. 82:2000;1
6. Li G.R., Feng J., Yue L., Carrier M., Nattel S. Circ. Res. 78:1996;689
7. Feng J., Wible B., Wang Z., Nattel S. Circ. Res. 80:1997;572
8. Amos G.J., Wettwer E., Metzger F., Li Q., Himmel H.M., Ravens U. J. Physiol. (Lond.). 491:1996;31
9. Brendel J., Peukert S. Expert. Opin. Ther. Patents. 12:2002;1589
10. Brendel J., Peukert S. Curr. Med. Chem. - CV & H Agents. 1:2003;273
11. Peukert S., Brendel J., Pirard B., Brüggemann A., Below P., Kleemann H.-W., Hemmerle H., Schmidt W. J. Med. Chem. 46:2003;486
12. (b) Aventis Pharma Deutschland GmbH, WO 0100573, 2001
13. -1). The energy was evaluated using the MacroModel 6.5 (www.schroedinger.com) implementation of the OPLS All-Atom force field. All the calculations were carried out in water, as modeled by the generalized Born/solvent accessible surface solvation model. The next step was to select representative sets of conformers, using hierarchical clustering on distances between all the potential pharmacophoric centers. Within each cluster, we chose the minimum energy conformation as input for the automated pharmacophore elucidation tool, DISCO (www.tripos.com). After visual inspection of the DISCO solutions, one of them was selected as query for 3D database searches with UNITY (www.tripos.com)
14. 2, calculated logPoctanol/water outside the - 2.0-5.0 range. QikProp 1.5 (www.schroedinger.com) was used to compute the physical properties
15. Lane C.F. Synthesis. 1975;135