Nonpeptide αvβ3 antagonists.: Part 11:: Discovery and preclinical evaluation of potent αvβ3 antagonists for the prevention and treatment of osteoporosis

被引：66

作者：

Coleman, PJ

Brashear, KM

Askew, BC

Hutchinson, JH

McVean, CA

Duong, LT

Feuston, BP

Fernandez-Metzler, C

Gentile, MA

Hartman, GD

Kimmel, DB

Leu, CT

Lipfert, L

Merkle, K

Pennypacker, B

Prueksaritanont, T

Rodan, GA

Wesolowski, GA

Rodan, SB

Duggan, ME

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Bone Biol & Osteporosis Res, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Drug Metab & Pharmacol, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Mol Syst, West Point, PA 19486 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 20期

关键词：

D O I：

10.1021/jm049874c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (IC50 = 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.

引用

页码：4829 / 4837

页数：9

共 35 条

[1] Non-peptide αvβ3 antagonists.: Part 5:: Identification of potent RGD mimetics incorporating 2-aryl β-amino acids as aspartic acid replacements [J].

Brashear, KM ;

Hunt, CA ;

Kucer, BT ;

Duggan, ME ;

Hartman, GD ;

Rodan, GA ;

Rodan, SB ;

Leu, CT ;

Prueksaritanont, T ;

Fernandez-Metzler, C ;

Barrish, A ;

Homnick, CF ;

Hutchinson, JH ;

Coleman, PJ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (23) :3483-3486

[2] Nonpeptide αvβ3 antagonists.: Part 10:: In vitro and in vivo evaluation of a potent 7-methyl substituted tetrahydro-[1,8]naphthyridine derivative [J].

Breslin, MJ ;

Duggan, ME ;

Halczenko, W ;

Hartman, GD ;

Duong, LT ;

Fernandez-Metzler, C ;

Gentile, MA ;

Kimmel, DB ;

Leu, CT ;

Merkle, K ;

Prueksaritanont, T ;

Rodan, GA ;

Rodan, SB ;

Hutchinson, JH .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (17) :4515-4518

[3]

Coleman PJ, 2002, EXPERT OPIN THER PAT, V12, P1009

[4] Non-peptide αvβ3 antagonists.: Part 4:: Potent and orally bioavailable chain-shortened RGD mimetics [J].

Coleman, PJ ;

Askew, BC ;

Hutchinson, JH ;

Whitman, DB ;

Perkins, JJ ;

Hartman, GD ;

Rodan, GA ;

Leu, CT ;

Prueksaritanont, T ;

Fernandez-Metzler, C ;

Merkle, KM ;

Lynch, R ;

Lynch, JJ ;

Rodan, SB ;

Duggan, ME .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (17) :2463-2465

[5] Non-peptide αvβ3 antagonists.: Part 3:: Identification of potent RGD mimetics incorporating novel β-amino acids as aspartic acid replacements [J].

Coleman, PJ ;

Brashear, KM ;

Hunt, CA ;

Hoffman, WF ;

Hutchinson, JH ;

Breslin, MJ ;

McVean, CA ;

Askew, BC ;

Hartman, GD ;

Rodan, SB ;

Rodan, GA ;

Leu, CT ;

Prueksaritanont, T ;

Fernandez-Metzler, C ;

Ma, B ;

Libby, LA ;

Merkle, KM ;

Stump, GL ;

Wallace, AA ;

Lynch, JJ ;

Lynch, R ;

Duggan, ME .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (01) :31-34

[6] Syntheses of 5-and 6-[2,3]-dihydrobenzofuran β-amino acids [J].

Coleman, PJ ;

Hutchinson, JH ;

Hunt, CA ;

Lu, P ;

Delaporte, E ;

Rushmore, T .

TETRAHEDRON LETTERS, 2000, 41 (31) :5803-5806

[7] PREPARATION OF PROTECTED TRANS-OLEFINIC DIPEPTIDE ISOSTERES [J].

COX, MT ;

HEATON, DW ;

HORBURY, J .

JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1980, (17) :799-800

[8] Antibody to beta(3) integrin inhibits osteoclast-mediated bone resorption in the thyroparathyroidectomized rat [J].

Crippes, BA ;

Engleman, VW ;

Settle, SL ;

Delarco, J ;

Ornberg, RL ;

Helfrich, MH ;

Horton, MA ;

Nickols, GA .

ENDOCRINOLOGY, 1996, 137 (03) :918-924

[9] Highly regioselective Friedlander annulations with unmodified ketones employing novel amine catalysts: Syntheses of 2-substituted quinolines, 1,8-naphthyridines, and related heterocycles [J].

Dormer, PG ;

Eng, KK ;

Farr, RN ;

Humphrey, GR ;

McWilliams, JC ;

Reider, PJ ;

Sager, JW ;

Volante, RP .

JOURNAL OF ORGANIC CHEMISTRY, 2003, 68 (02) :467-477

[10] Nonpeptide αvβ3 antagonists.: 1.: Transformation of a potent, integrin-selective αIIbβ3 antagonist into a potent αvβ3 antagonist [J].

Duggan, ME ;

Duong, LT ;

Fisher, JE ;

Hamill, TG ;

Hoffman, WF ;

Huff, JR ;

Ihle, NC ;

Leu, CT ;

Nagy, RM ;

Perkins, JJ ;

Rodan, SB ;

Wesolowski, G ;

Whitman, DB ;

Zartman, AE ;

Rodan, GA ;

Hartman, GD .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (20) :3736-3745

← 1 2 3 4 →