doi:10.1016/j.bmcl.2008.04.047 
Copyright © 2008 Elsevier Ltd All rights reserved.
Discovery of orally active pyrrolopyridine- and aminopyridine-based Met kinase inhibitors
Zhen-Wei Cai
, a, 
, Donna Weia, Gretchen M. Schroedera, Lyndon A.M. Corneliusa, Kyoung Kima, Xiao-Tao Chena, Robert J. Schmidta, David K. Williamsa, John S. Tokarskia, Yongmi Ana, John S. Sacka, Veeraswamy Mannea, Amrita Kamatha, Yueping Zhanga, Punit Marathea, John T. Hunta, Louis J. Lombardoa, Joseph Fargnolia and Robert M. Borzilleria
aBristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA
Received 29 February 2008;
revised 21 April 2008;
accepted 22 April 2008.
Available online 25 April 2008.
References and further reading may be available for this article. To view references and further reading you must
purchase this article.
Abstract
A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.
Graphical abstract
A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR studies led to the discovery of compounds 3b and 20b, which demonstrated significant antitumor activity in a human gastric carcinoma xenograft model.
Keywords: Met; Receptor tyrosine kinase; Protein kinase inhibitors
Article Outline
- References
Figure 1. Met kinase inhibitors derived from different scaffolds.
Scheme 1. Reagents and conditions: (a) PyBOP, DIPEA, THF, rt, 75–90%; (b) DCM, rt, 65–75%.
Scheme 2. Reagents and conditions: (a) 2-bromoacetyl chloride, AlCl3, DCE, rt, 78%; (b) R1R2NH, THF, rt, 65–90%; (c) Zn, NH4Cl, MeOH/THF, rt, 70–95%; (d) 6, DCM, rt, 30–55%; (e) trichloroacetyl chloride, AlCl3, DCE, rt, 76%; (f) 3-aminomethylpyridine, DMF, rt, 61%; (g) 1 N NaOH, MeOH, 61%; (h) DIBAL, THF, 0 °C, 53%.
Scheme 3. Reagents and conditions: (a) NaH, SEM-Cl, DMF, −40 to 0 °C; (b) NBS, CH3CN, 0 °C to rt, 92% for two steps; (c) aryl boronic acid, Pd(PPh3)4, K3PO4, EtOH, toluene, 80 °C, 75–82%; (d) Zn, NH4Cl, MeOH/THF, rt, 80–95%; (e) TBAF, THF, 50 °C, 78–80%; (f) 6, DCM, rt, 30–55%; (g) 3-ethynylpyridine, Pd(PPh3)4, CuI, Et3N, DMF, 85 °C, 61%; (h) KOtBu, NMP, 80 °C, 80%.
Scheme 4. Reagents and conditions: (a) R6–CCH, Pd(PPh3)4, CuI, Et3N, DMF, 85 °C, 50–80%; (b) Zn, NH4Cl, MeOH/THF, rt, 70–95%; (c) 6, DCM, rt, 18–55%; (d) TBAF, THF, −30 to 0 °C, 88%; (e) 35% TFA in DCM, rt, 60%.
Figure 2. A close-up of the X-ray co-crystal structure of 2b (in green) and 3b (in magenta) in the Met ATP binding site (only the protein bound with 2b is shown). The binding region of the protein is rendered in a surface representation and colored by the associated atoms of the protein (carbon: white, oxygen: red, nitrogen: blue, and sulfur: orange). PDB code: 3CTJ for 2b and 3CTH for 3b.
Figure 3. Antitumor activity of 20b against GTL-16 xenografts implanted in the athymic mice. Arrows indicate dosing.
Table 1.
In vitro activities of compounds 1b, 2, and 3a
a For assay conditions, see Ref.
8.
Table 2.
SAR of pyrrolopyridine seriesa
a For assay conditions, see Ref.
8.
Table 3.
SAR of aminopyridine seriesa
a For assay conditions, see Ref.
8.
Table 4.
Metabolic stability and mouse exposure data following oral administration of selected compoundsa
a Compounds at 3 μM incubated in 10 mg of protein (HLM or MLM) for 10 min.
b Dosed at 50 mg/kg, all values are means of at least three mice.
c Vehicle: PEG400/water (1:1).
Table 5.
Antitumor activities of compounds 20b, 3b, and 26c in the GTL-16 xenograft model in micea
a Vehicle: PEG400/water (1:1).
Abstract
Purchase PDF (275 K)
E-mail Article
Add to my Quick Links
Cited By in Scopus (1)
Purchase PDF (296 K)
