title: Potent and selective ET-A antagonists. 2. Discovery and evaluation of potent and water soluble N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives.
abstract: In the preceding article,(1) we outlined the discovery and structure-activity relationship of a potent and selective ET(A) receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ET(A) receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ET(A) receptor (K(i) for ET(A) receptor: 0.015 +/- 0.004 nM; for ET(B) receptor: 41 +/- 21 nM).
authors.affiliation: Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50 Kawagishi, Toda, Saitama, Japan 335-8505.
authors.forename: H
authors.initials: H
authors.lastname: Morimoto
authors.forename: N
authors.initials: N
authors.lastname: Ohashi
authors.forename: H
authors.initials: H
authors.lastname: Shimadzu
authors.forename: E
authors.initials: E
authors.lastname: Kushiyama
authors.forename: H
authors.initials: H
authors.lastname: Kawanishi
authors.forename: T
authors.initials: T
authors.lastname: Hosaka
authors.forename: Y
authors.initials: Y
authors.lastname: Kawase
authors.forename: K
authors.initials: K
authors.lastname: Yasuda
authors.forename: K
authors.initials: K
authors.lastname: Kikkawa
authors.forename: R
authors.initials: R
authors.lastname: Yamauchi-Kohno
authors.forename: K
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D014867:Water
chemical_list: D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D013449:Sulfonamides; C113972:T 0201; D014867:Water