Evidence map›Paper›PMID 26005532›Full record

ArticleACS medicinal chemistry letters2015

Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement.

Harry R Chobanian, Barbara Pio, Yan Guo, Hong Shen, Mark A Huffman, Maria Madeira, Gino Salituro, Jenna L Terebetski, James Ormes, Nina Jochnowitz and 10 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in ACS medicinal chemistry letters, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
0.4field-weighted citation impact, top 32% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 7 citations in OpenAlex.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors at 1 institution in 1 country.

Harry R ChobanianDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Barbara PioDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Yan GuoDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Hong ShenDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Mark A HuffmanDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Maria MadeiraDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Gino SalituroDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Jenna L TerebetskiDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
James OrmesDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Nina JochnowitzDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Lizbeth HoosDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Yuchen ZhouDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Dale LewisDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Brian HawesDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Lyndon MitnaulDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Kim O'NeillDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Kenneth EllsworthDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Liangsu WangDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Tesfaye BiftuDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Joseph L DuffyDepartments of Medicinal Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, Preclinical Development, Pharmacology, and Thrombosis, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Merck & Co., Inc., Rahway, NJ, USA (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

dabigatranprolineserine proteaseThrombinthrombosiswarfarin

Identifiers

PMID26005532
PMCPMC4434479
OpenAlexW2331609248

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.