Nonpeptide alphavbeta3 antagonists. Part 11: discovery and preclinical evaluation of potent alphavbeta3 antagonists for the prevention and treatment of osteoporosis

Journal of Medicinal Chemistry
Paul J ColemanMark E Duggan

Abstract

3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.

References

Mar 12, 1998·The New England Journal of Medicine·R Eastell
Jul 31, 1998·Frontiers in Bioscience : a Journal and Virtual Library·L T Duong, G A Rodan
Jun 18, 2002·The Journal of Pharmacology and Experimental Therapeutics·Sandra J HoffmanGeorge Stroup
Dec 13, 2002·Journal of Medicinal Chemistry·Bradley P FeustonSevgi B Rodan

❮ Previous
Next ❯

Citations

Apr 19, 2011·Breast Cancer Research and Treatment·Dong-Mei Li, Yu-Mei Feng
Dec 5, 2009·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Sylvie KossodoBohumil Bednar
Mar 5, 2005·Bioorganic & Medicinal Chemistry Letters·Amy E ZartmanRobert S Meissner
Sep 28, 2013·Phytochemistry·Keisuke NishikawaMitsuru Shindo
Dec 2, 2010·Nature Reviews. Drug Discovery·Dennis A SmithEdward H Kerns
Mar 26, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Patrick M WinterGregory M Lanza
Oct 7, 2008·Investigative Radiology·Michal LijowskiGregory M Lanza
Feb 1, 2008·Expert Opinion on Drug Discovery·Ramesh N Patel
Jan 23, 2008·Expert Opinion on Therapeutic Targets·Sengen Sun
Jan 28, 2015·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Petra SchulzCarsten Grötzinger
Apr 4, 2017·Chemistry : a European Journal·Jan ReutzelArmin Geyer
Dec 6, 2005·Journal of Biochemical and Biophysical Methods·Margery A ChaikinCarl L Manthey
Dec 8, 2014·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Mohammad Faheem KhanRakesh Maurya
Mar 10, 2017·Bioorganic & Medicinal Chemistry Letters·Padam KumarRakesh Maurya
Nov 30, 2016·Pest Management Science·Caleb W HolyokeKenneth A Hughes
Sep 26, 2017·Angewandte Chemie·Richard J D HatleyPauline T Lukey
Mar 23, 2010·Expert Opinion on Therapeutic Patents·Keiichi Masuya, Naoki Teno
Jan 26, 2012·Current Osteoporosis Reports·Sanford Baim, William D Leslie
Mar 14, 2014·American Journal of Therapeutics·Cui-Cui SunZu-Hua Gao
Jul 11, 2014·Anti-cancer Drugs·Cui-Cui SunZu-Hua Gao
Dec 13, 2006·Clinical Science·T John Martin, Ego Seeman
Dec 7, 2011·Contrast Media & Molecular Imaging·Stefania LanzardoGuido Forni
Jun 9, 2015·Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology·Lei Xi, Hubei Jiang
Oct 28, 2011·Journal of Biophotonics·Yared TekabeLynne Johnson
Nov 10, 2015·Archiv der Pharmazie·Alka MadaanManu Jaggi
Jan 24, 2021·Scientific Reports·Ji ZhangMasahisa Handa
Jul 30, 2014·Advanced Drug Delivery Reviews·Lihong BuZhen Cheng
Oct 29, 2009·Journal of Medicinal Chemistry·Vincent ReratJacqueline Marchand-Brynaert
Oct 10, 2006·Bioorganic & Medicinal Chemistry Letters·Guang-Zhi ZengRong-Tao Li
Sep 10, 2019·Journal of Medicinal Chemistry·Niall A AndersonSimon J F Macdonald
Nov 2, 2007·Journal of Medicinal Chemistry·Jayanta ChatterjeeHorst Kessler

❮ Previous
Next ❯

Related Concepts

Related Feeds

Adhesion Molecules in Health and Disease

Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.