Literature DB >> 24900270

Synthesis and Evaluation of the Metabolites of AMG 221, a Clinical Candidate for the Treatment of Type 2 Diabetes.

Aiwen Li1, Chester C Yuan1, David Chow1, Michelle Chen1, Maurice G Emery1, Clarence Hale1, Xiping Zhang1, Raju Subramanian1, David J St Jean1, Renee Komorowski1, Murielle Véniant1, Minghan Wang1, Christopher Fotsch1.   

Abstract

All eight of the major active metabolites of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221, compound 1), an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 that has entered the clinic for the treatment of type 2 diabetes, were synthetically prepared and confirmed by comparison with samples generated in liver microsomes. After further profiling, we determined that metabolite 2 was equipotent to 1 on human 11β-HSD1 and had lower in vivo clearance and higher bioavailability in rat and mouse. Compound 2 was advanced into a pharmacodynamic model in mouse where it inhibited adipose 11β-HSD1 activity.

Entities:  

Keywords:  11β-HSD1 inhibitors; AMG 221; clinical candidate; metabolites

Year:  2011        PMID： 24900270      PMCID： PMC4018091          DOI： 10.1021/ml2001467

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  7 in total

Review 1.  Discovering drugs through biological transformation: role of pharmacologically active metabolites in drug discovery.

Authors:  Aberra Fura; Yue-Zhong Shu; Mingshe Zhu; Ronald L Hanson; Vikram Roongta; W Griffith Humphreys
Journal:  J Med Chem       Date:  2004-08-26       Impact factor: 7.446

Review 2.  Role of pharmacologically active metabolites in drug discovery and development.

Authors:  Aberra Fura
Journal:  Drug Discov Today       Date:  2006-02       Impact factor: 7.851

3.  Metabolites in safety testing: metabolite identification strategies in discovery and development.

Authors:  Angus N R Nedderman
Journal:  Biopharm Drug Dispos       Date:  2009-05       Impact factor: 1.627

4.  Nucleophilic fluorination of triflates by tetrabutylammonium bifluoride.

Authors:  Kyu-Young Kim; Bong Chan Kim; Hee Bong Lee; Hyunik Shin
Journal:  J Org Chem       Date:  2008-09-23       Impact factor: 4.354

5.  Discovery of a potent, orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor for clinical study: identification of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221).

Authors:  Murielle M Véniant; Clarence Hale; Randall W Hungate; Kyung Gahm; Maurice G Emery; Janan Jona; Smriti Joseph; Jeffrey Adams; Andrew Hague; George Moniz; Jiandong Zhang; Michael D Bartberger; Vivian Li; Rashid Syed; Steven Jordan; Renée Komorowski; Michelle M Chen; Rod Cupples; Ki Won Kim; David J St Jean; Lars Johansson; Martin A Henriksson; Meredith Williams; Jerk Vallgårda; Christopher Fotsch; Minghan Wang
Journal:  J Med Chem       Date:  2010-06-10       Impact factor: 7.446

6.  Population pharmacokinetic/pharmacodynamic model of subcutaneous adipose 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity after oral administration of AMG 221, a selective 11β-HSD1 inhibitor.

Authors:  John P Gibbs; Maurice G Emery; Ian McCaffery; Brian Smith; Megan A Gibbs; Anna Akrami; John Rossi; Katherine Paweletz; Marc R Gastonguay; Edgar Bautista; Minghan Wang; Riccardo Perfetti; Oranee Daniels
Journal:  J Clin Pharmacol       Date:  2010-07-27       Impact factor: 3.126

7.  A chiral chelating diene as a new type of chiral ligand for transition metal catalysts: its preparation and use for the rhodium-catalyzed asymmetric 1,4-addition.

Authors:  Tamio Hayashi; Kazuhito Ueyama; Norihito Tokunaga; Kazuhiro Yoshida
Journal:  J Am Chem Soc       Date:  2003-09-24       Impact factor: 15.419
  7 in total
  2 in total

1.  Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes.

Authors:  Zhao-Kui Wan; Eva Chenail; Huan-Qiu Li; Manus Ipek; Jason Xiang; Vipin Suri; Seung Hahm; Joel Bard; Kristine Svenson; Xin Xu; Xianbin Tian; Mengmeng Wang; Xiangping Li; Christian E Johnson; Ariful Qadri; Darrell Panza; Mylene Perreault; Tarek S Mansour; James F Tobin; Eddine Saiah
Journal:  ACS Med Chem Lett       Date:  2012-11-23       Impact factor: 4.345

2.  Gold(I)-Catalyzed Cycloisomerization of 3-Alkoxyl-1,6-diynes: A Facile Access to Bicyclo[2.2.1]hept-5-en-2-ones.

Authors:  Chao Hu; Tao Wang; Matthias Rudolph; Thomas Oeser; Abdullah M Asiri; A Stephen K Hashmi
Journal:  Angew Chem Int Ed Engl       Date:  2020-03-24       Impact factor: 15.336
  2 in total

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