Literature DB >> 26819671

Optimizing Ligand Efficiency of Selective Androgen Receptor Modulators (SARMs).

Anthony L Handlon1, Lee T Schaller1, Lisa M Leesnitzer1, Raymond V Merrihew1, Chuck Poole1, John C Ulrich1, Joseph W Wilson1, Rodolfo Cadilla1, Philip Turnbull1.   

Abstract

A series of selective androgen receptor modulators (SARMs) containing the 1-(trifluoromethyl)benzyl alcohol core have been optimized for androgen receptor (AR) potency and drug-like properties. We have taken advantage of the lipophilic ligand efficiency (LLE) parameter as a guide to interpret the effect of structural changes on AR activity. Over the course of optimization efforts the LLE increased over 3 log units leading to a SARM 43 with nanomolar potency, good aqueous kinetic solubility (>700 μM), and high oral bioavailability in rats (83%).

Entities:  

Keywords:  LLE; SARM; androgen receptor; ligand efficiency; selective androgen receptor modulator

Year:  2015        PMID： 26819671      PMCID： PMC4716610          DOI： 10.1021/acsmedchemlett.5b00377

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


  12 in total

1.  3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy}phenyl)propanoic acid: a brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2).

Authors:  Rowena V Cube; Jean-Michel Vernier; John H Hutchinson; Michael F Gardner; Joyce K James; Blake A Rowe; Herve Schaffhauser; Lorrie Daggett; Anthony B Pinkerton
Journal:  Bioorg Med Chem Lett       Date:  2005-05-02       Impact factor: 2.823

Review 2.  Selective androgen receptor modulators in drug discovery: medicinal chemistry and therapeutic potential.

Authors:  Rodolfo Cadilla; Philip Turnbull
Journal:  Curr Top Med Chem       Date:  2006       Impact factor: 3.295

3.  Validity of ligand efficiency metrics.

Authors:  Christopher W Murray; Daniel A Erlanson; Andrew L Hopkins; György M Keserü; Paul D Leeson; David C Rees; Charles H Reynolds; Nicola J Richmond
Journal:  ACS Med Chem Lett       Date:  2014-05-09       Impact factor: 4.345

Review 4.  The role of ligand efficiency metrics in drug discovery.

Authors:  Andrew L Hopkins; György M Keserü; Paul D Leeson; David C Rees; Charles H Reynolds
Journal:  Nat Rev Drug Discov       Date:  2014-02       Impact factor: 84.694

5.  The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial.

Authors:  James T Dalton; Kester G Barnette; Casey E Bohl; Michael L Hancock; Domingo Rodriguez; Shontelle T Dodson; Ronald A Morton; Mitchell S Steiner
Journal:  J Cachexia Sarcopenia Muscle       Date:  2011-08-02       Impact factor: 12.910

6.  The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men.

Authors:  Shehzad Basaria; Lauren Collins; E Lichar Dillon; Katie Orwoll; Thomas W Storer; Renee Miciek; Jagadish Ulloor; Anqi Zhang; Richard Eder; Heather Zientek; Gilad Gordon; Syed Kazmi; Melinda Sheffield-Moore; Shalender Bhasin
Journal:  J Gerontol A Biol Sci Med Sci       Date:  2012-03-28       Impact factor: 6.053

Review 7.  Sarcopenia of aging and its metabolic impact.

Authors:  Helen Karakelides; K Sreekumaran Nair
Journal:  Curr Top Dev Biol       Date:  2005       Impact factor: 4.897

Review 8.  Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs).

Authors:  Wenqing Gao; James T Dalton
Journal:  Drug Discov Today       Date:  2007-02-07       Impact factor: 7.851

9.  Are we closer to having drugs to treat muscle wasting disease?

Authors:  John E Morley; Stephan von Haehling; Stefan D Anker
Journal:  J Cachexia Sarcopenia Muscle       Date:  2014-05-28       Impact factor: 12.910

10.  Prevalence, incidence and clinical impact of cachexia: facts and numbers-update 2014.

Authors:  Stephan von Haehling; Stefan D Anker
Journal:  J Cachexia Sarcopenia Muscle       Date:  2014-12       Impact factor: 12.910
View more
  5 in total

Review 1.  Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications.

Authors:  Zachary J Solomon; Jorge Rivera Mirabal; Daniel J Mazur; Taylor P Kohn; Larry I Lipshultz; Alexander W Pastuszak
Journal:  Sex Med Rev       Date:  2018-11-30

2.  Identifying environmental chemicals as agonists of the androgen receptor by using a quantitative high-throughput screening platform.

Authors:  Caitlin Lynch; Srilatha Sakamuru; Ruili Huang; Diana A Stavreva; Lyuba Varticovski; Gordon L Hager; Richard S Judson; Keith A Houck; Nicole C Kleinstreuer; Warren Casey; Richard S Paules; Anton Simeonov; Menghang Xia
Journal:  Toxicology       Date:  2017-05-04       Impact factor: 4.221

Review 3.  Understanding and managing the suppression of spermatogenesis caused by testosterone replacement therapy (TRT) and anabolic-androgenic steroids (AAS).

Authors:  Ankit Desai; Musaab Yassin; Axel Cayetano; Tharu Tharakan; Channa N Jayasena; Suks Minhas
Journal:  Ther Adv Urol       Date:  2022-06-26

Review 4.  Selective androgen receptor modulators: the future of androgen therapy?

Authors:  Andrew R Christiansen; Larry I Lipshultz; James M Hotaling; Alexander W Pastuszak
Journal:  Transl Androl Urol       Date:  2020-03

Review 5.  Androgens and Their Role in Regulating Sex Differences in the Hypothalamic/Pituitary/Adrenal Axis Stress Response and Stress-Related Behaviors.

Authors:  Julietta A Sheng; Sarah M L Tan; Taben M Hale; Robert J Handa
Journal:  Androg Clin Res Ther       Date:  2021-12-23
  5 in total

北京卡尤迪生物科技股份有限公司 © 2022-2023.