Novel selective PPARδ agonists:: Optimization of activity by modification of alkynylallylic moiety

被引：13

作者：

Havranek, Miroslav

Sauerberg, Per

Mogensen, John P.

Kratina, Pavel

Jeppesen, Claus B.

Pettersson, Ingrid

Pihera, Pavel

机构：

[1] VUFB Sro, RE&D, Prague 18066, Czech Republic

[2] Novo Nordisk AS, DK-2670 Malov, Denmark

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 15期

关键词：

nuclear receptor; peroxisome proliferator-activated receptor delta; PPAR agonists; hydroalumination; substituted allyl alcohols;

D O I：

10.1016/j.bmcl.2007.05.051

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPAR delta activators. The alkynylallylic moiety was synthesized from alkyn-l-ols by hydroalumination followed by a cross-coupling reaction. Series of active compounds 6 were obtained by stepwise changing the structure of the known PPARpan agonist 5 into Y-shaped compounds. The most active and selective compound, 6f, had a PPAR delta potency of 0.13 mu M, which is 50-fold more potent than compound 5. (c) 2007 Elsevier Ltd. All rights reserved.

引用

页码：4144 / 4149

页数：6

共 25 条

[1]

Auwerx J, 1999, CELL, V97, P161

[2] Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: A retrospective review of randomly selected medical records [J].

Boyle, PJ ;

King, AB ;

Olansky, L ;

Marchetti, A ;

Lau, H ;

Magar, R ;

Martin, J .

CLINICAL THERAPEUTICS, 2002, 24 (03) :378-396

[3] A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus [J].

Chilcott, J ;

Tappenden, P ;

Jones, ML ;

Wight, JP .

CLINICAL THERAPEUTICS, 2001, 23 (11) :1792-1823

[4]

CORREY EJ, 1967, J AM CHEM SOC, V89, P4245

[5] AN EFFICIENT, ENANTIOSELECTIVE SYNTHESIS OF THE TAXOL SIDE-CHAIN [J].

DENIS, JN ;

GREENE, AE ;

SERRA, AA ;

LUCHE, MJ .

JOURNAL OF ORGANIC CHEMISTRY, 1986, 51 (01) :46-50

[6] Process development and scale-up of the PPAR agonist NNC 61-4655 [J].

Deussen, HJ ;

Jeppesen, L ;

Schärer, N ;

Junager, F ;

Bentzen, B ;

Weber, B ;

Weil, V ;

Mozer, SJ ;

Sauerberg, P .

ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2004, 8 (03) :363-371

[7] 1,3,5-Trisubstituted aryls as highly selective PPARδ agonists [J].

Epple, R ;

Azimioara, M ;

Russo, R ;

Bursulaya, B ;

Tian, SS ;

Gerken, A ;

Iskandar, M .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (11) :2969-2973

[8] 3,4,5-trisubstituted isoxazoles as novel PPARδ agonists:: Part 1 [J].

Epple, Robert ;

Russo, Ross ;

Azimioara, Mihai ;

Cow, Christopher ;

Xie, Yongping ;

Wang, Xing ;

Wityak, John ;

Karanewsky, Don ;

Gerken, Andrea ;

Iskandar, Maya ;

Saez, Enrique ;

Seidel, H. Martin ;

Tian, Shin-Shay .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (16) :4376-4380

[9] 3,4,5-Trisubstituted isoxazoles as novel PPARδ agonists.: Part 2 [J].

Epple, Robert ;

Azimioara, Mihai ;

Russo, Ross ;

Xie, Yongping ;

Wang, Xing ;

Cow, Christopher ;

Wityak, John ;

Karanewsky, Don ;

Bursulaya, Badry ;

Kreusch, Andreas ;

Tuntland, Tove ;

Gerken, Andrea ;

Iskandar, Maya ;

Saez, Enrique ;

Seidel, H. Martin ;

Tian, Shin-Shay .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (21) :5488-5492

[10] Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy [J].

Friesner, RA ;

Banks, JL ;

Murphy, RB ;

Halgren, TA ;

Klicic, JJ ;

Mainz, DT ;

Repasky, MP ;

Knoll, EH ;

Shelley, M ;

Perry, JK ;

Shaw, DE ;

Francis, P ;

Shenkin, PS .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (07) :1739-1749

← 1 2 3 →