title: New non-peptide endothelin-A receptor antagonists: synthesis, biological properties, and structure-activity relationships of 5-(dimethylamino)-N-pyridyl-,-N-pyrimidinyl-,-N-pyridazinyl-, and -N-pyrazinyl-1-naphthalenesulfonamides.
abstract: Use of automated synthesis led to the discovery of several 6-membered nitrogen heterocycles as replacements for the N-isoxazolyl substituent present in the 1-naphthalenesulfonamides endothelin-A (ETA) antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesu lfo namides (BMS 182874). In each of these heterocycles, a small substituent such as halogen para to the position of attachment to the sulfonamide nitrogen atom was found to be advantageous for ETA receptor affinity. Of these heterocycles, 2-pyrazines offered the greatest scope for improving receptor affinity. Optimization of the substituents at the 3- and 5-positions in the pyrazine ring led to potent, ETA-selective compounds such as 5-(dimethylamino)-N-(5-chloro-3-methoxy-2-pyrazinyl)-1- naphthalenesulfonamides (7m, ETA pIC50 8.1). When dosed orally at 10 mg/kg to conscious, normotensive rats infused with big ET-1, compounds such as 7m showed significant inhibition of the pressor response with a duration of effect lasting for the 5-h course of the experiment.
authors.affiliation: Cardiovascular and Musculoskeletal Department, ZENECA Pharmaceuticals, Macelesfield, Cheshire, U.K.
authors.forename: R H
authors.initials: RH
authors.lastname: Bradbury
authors.forename: C
authors.initials: C
authors.lastname: Bath
authors.forename: R J
authors.initials: RJ
authors.lastname: Butlin
authors.forename: M
authors.initials: M
authors.lastname: Dennis
authors.forename: C
authors.initials: C
authors.lastname: Heys
authors.forename: S J
authors.initials: SJ
authors.lastname: Hunt
authors.forename: R
authors.initials: R
authors.lastname: James
authors.forename: A A
authors.initials: AA
authors.lastname: Mortlock
authors.forename: N F
authors.initials: NF
authors.lastname: Sumner
authors.forename: E K
authors.initials: EK
authors.lastname: Tang
authors.forename: B
authors.initials: B
authors.lastname: Telford
authors.forename: E
authors.initials: E
authors.lastname: Whiting
authors.forename: C
authors.initials: C
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003619:Dansyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006168:Guinea Pigs; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D011485:Protein Binding; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide