Ohlstein E H, Nambi P, Lago A, Hay D W, Beck G, Fong K L, Eddy E P, Smith P, Ellens H, Elliott J D
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
J Pharmacol Exp Ther. 1996 Feb;276(2):609-15.
This study describes the pharmacological characterization of SB 217242, a highly potent orally bioavailable nonpeptide antagonist of both endothelin type A (ETA) and endothelin type B (ETB) receptors. In human cloned ETA and ETB receptors, SB 217242 produced concentration-dependent displacement of [125]I-endothelin-1 (ET-1) in both receptor subtypes with Ki values of 1.1 and 111 nM, respectively. SB 217242 produced concentration-dependent, parallel rightward shifts in the ET-1 concentration-response curves in rat isolated aorta and human isolated pulmonary artery (ETA receptor-mediated vascular contraction) with Kb values of 4.4 and 5.0 nM, respectively. SB 217242 was 4-, 62- and 125-fold more potent as an ETA receptor antagonist than the previously reported compounds BQ-123, PD 142893 and Ro 46-2005, respectively. SB 217242 (10 microM) did not produce significant effects against contraction produced by other vasoactive agents. SB 217242 produced concentration-dependent antagonism of responses produced by ETB receptor activation as demonstrated by antagonism of sarafotoxin S6c-mediated contraction in the rabbit isolated pulmonary artery with a Kb value of 352 nM. In vitro cell monolayers of Caco-2 cells had high permeability to SB 217242. In vivo pharmacokinetics in the rat confirmed that SB 217242 was rapidly absorbed from the gastrointestinal tract with a bioavailability of 66%. The SB 217242 plasma half-life in rats after intraduodenal administration was 3.3 hr, with a systemic clearance of 27.3 ml/min/kg. Orally administered SB 217242 (0.3-30 mg/kg) produced dose-dependent inhibition of the pressor response to exogenous ET-1 in conscious rats; with a dose of 30 mg/kg p.o., inhibition was observed for at least 5.5 hr. The present study demonstrates that SB 217242 is a highly potent antagonist of both ETA and ETB receptors. In addition, SB 217242 has high in vitro permeability and high oral bioavailability. SB 217242 represents a new orally active pharmacological tool that should assist in the elucidation of the chronic role of endothelin in pathophysiology.
本研究描述了SB 217242的药理学特性，它是一种高效的口服生物可利用的非肽类内皮素A（ETA）和内皮素B（ETB）受体拮抗剂。在人克隆的ETA和ETB受体中，SB 217242在两种受体亚型中均产生浓度依赖性的[125]I-内皮素-1（ET-1）置换，其Ki值分别为1.1和111 nM。SB 217242在大鼠离体主动脉和人离体肺动脉（ETA受体介导的血管收缩）中使ET-1浓度-反应曲线产生浓度依赖性的平行右移，其Kb值分别为4.4和5.0 nM。作为ETA受体拮抗剂，SB 217242的效力分别比先前报道的化合物BQ-123、PD 142893和Ro 46-2005高4倍、62倍和125倍。SB 217242（10 microM）对其他血管活性药物引起的收缩没有显著影响。SB 217242对ETB受体激活产生的反应具有浓度依赖性拮抗作用，如在兔离体肺动脉中对蛙皮素S6c介导的收缩的拮抗作用所示，其Kb值为352 nM。Caco-2细胞的体外细胞单层对SB 217242具有高渗透性。大鼠体内药代动力学证实SB 217242能迅速从胃肠道吸收，生物利用度为66%。十二指肠内给药后，SB 217242在大鼠体内的血浆半衰期为3.3小时，全身清除率为27.3 ml/min/kg。口服SB 217242（0.3 - 30 mg/kg）对清醒大鼠对外源性ET-1的升压反应产生剂量依赖性抑制；口服剂量为30 mg/kg时，至少5.5小时内可观察到抑制作用。本研究表明SB 217242是ETA和ETB受体的高效拮抗剂。此外，SB 217242具有高体外渗透性和高口服生物利用度。SB 217242代表一种新的口服活性药理学工具，应有助于阐明内皮素在病理生理学中的慢性作用。
