title: Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement.
abstract: Modification of the previously disclosed (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1-((R)-2-hydroxy-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide 2 by optimization of the P3 group afforded novel, low molecular weight thrombin inhibitors. Heterocycle replacement of the hydroxyl functional group helped maintain thrombin in vitro potency while improving the chemical stability and pharmacokinetic profile. These modifications led to the identification of compound 10, which showed excellent selectivity over related serine proteases as well as in vivo efficacy in the rat arteriovenous shunt. Compound 10 exhibited significantly improved chemical stability and pharmacokinetic properties over 2 and may be utilized as a structurally differentiated preclinical tool comparator to dabigatran etexilate (Pro-1) to interrogate the on- and off-target effects of oral direct thrombin inhibitors.
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Chobanian
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pio
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Huffman
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Madeira
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Gino
authors.initials: G
authors.lastname: Salituro
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Terebetski
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: James
authors.initials: J
authors.lastname: Ormes
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Nina
authors.initials: N
authors.lastname: Jochnowitz
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hoos
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Dale
authors.initials: D
authors.lastname: Lewis
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Hawes
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Lyndon
authors.initials: L
authors.lastname: Mitnaul
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Kim
authors.initials: K
authors.lastname: O'Neill
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ellsworth
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Liangsu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Tesfaye
authors.initials: T
authors.lastname: Biftu
authors.affiliation: Departments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Duffy
keywords: Thrombin; dabigatran; proline; serine protease; thrombosis; warfarin