Digoxin Chiral Isolates as Improved Pharmaceuticals

地高辛手性分离物作为改进的药物

• 批准号: 6880348
• 负责人: JOHN C SOMBERG
• 金额: $ 10.2万
• 依托单位: ACADEMIC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6880348
• 关键词: atrial fibrillation; chemical structure function; congestive heart failure; digoxin; dogs; dosage; drug adverse effect; drug screening /evaluation; electrocardiography; guinea pigs; heart conduction system; heart contraction; heart disorder chemotherapy; heart function; heart pharmacology; nonhuman therapy evaluation; protein isoforms; sodium potassium exchanging ATPase; stereoisomer

DESCRIPTION (provided by applicant): Digoxin is the first line pharmacologic therapy for CHF and AF. Digoxin increases cardiac contractility and blocks conduction through the AV node slowing the ventricular response to AF and thus slowing the rate of the beating ventricles permitting more time for the heart to fill. The recent Dig trial supports the use of digoxin in the treatment of CHF and the recent AFIRM trial supports the rate control strategy for AF treatment. Digoxin is believed to augment contractility by inhibition of NaK+ATP'ace as well as of AV node delay by this mechanism. However, the inhibition of NaK+ATP'ace is initiated by digoxin binding to the alpha subunit and three different subunits exist. Digoxin is a chiral molecule and it is possible that the chiral isolates of digoxin exhibit different binding affinities for the alpha subunits yielding different effects on cardiac contractility and AV node conduction. In preliminary studies we have been able to isolate two isomers and find differential effects on conduction and contractility. We propose to further expand the preliminary work, confirm the differential action on the two isolates in a second species; both requisite preliminary steps to developing the two compounds as independent pharmaceutical agents. Additionally we propose studies to identify the isolates as to chemical structure, determine their stability in vitro and in vivo as well as develop methods to increase the yield of the isolates at chiral separation. We further propose to determine the toxic to therapeutic ratio of the isolates to see if they offer an advantage to the racemate digoxin compound. The advantage would be a treatment for AF that did not cause cardiac augmentation and vasoconstriction or a treatment for CHF that does not cause heart rate slowing or conduction disturbances.

描述（由申请人提供）：地高辛是CHF和AF的一线药物治疗。地高辛增加心脏收缩力并阻断通过房室结的传导，减缓心室对AF的反应，从而减慢心室跳动的速率，使心脏有更多时间充盈。最近的Dig试验支持使用地高辛治疗CHF，最近的AFIRM试验支持AF治疗的心率控制策略。地高辛被认为通过抑制NaK+ATP'ace以及通过该机制抑制AV结延迟来增强收缩力。然而，NaK+ATP'ace的抑制是由地高辛与α亚基结合而启动的，并且存在三种不同的亚基。地高辛是一种手性分子，地高辛的手性分离物可能对α亚基表现出不同的结合亲和力，对心肌收缩力和房室结传导产生不同的影响。在初步研究中，我们已经能够分离出两种异构体，并发现对传导和收缩性的不同影响。我们建议进一步扩大初步工作，确认对第二个物种中的两种分离株的差异作用;这两个步骤都是开发这两种化合物作为独立药剂所必需的初步步骤。此外，我们提出的研究，以确定分离物的化学结构，确定其在体外和体内的稳定性，以及开发方法，以增加在手性分离的分离物的产量。我们还建议确定分离株的毒性与治疗比，以确定它们是否比消旋地高辛化合物更有优势。其优点是AF治疗不会引起心脏增强和血管收缩，或CHF治疗不会引起心率减慢或传导障碍。