Bioorganic & Medicinal Chemistry Letters 15 (2005) 1749–1753
Isosteric ramatroban analogs: selective and potent
CRTH-2 antagonists
Michael J. Robarge,* David C. Bom, L. Nathan Tumey, Norbert Varga,
Elizabeth Gleason, Daniel Silver, Jianping Song, Steven M. Murphy, George Ekema,
Chris Doucette, Doug Hanniford, Marc Palmer, Gary Pawlowski, Joel Danzig,
Margaret Loftus, Karen Hunady, Bruce A. Sherf, Robert W. Mays,
Alain Stricker-Krongrad, Kurt R. Brunden, John J. Harrington and Youssef L. Bennani
Athersys, Inc., Medicinal Chemistry, 3201 Carnegie Avenue, Cleveland, OH 441152634, USA
Received 6 August 2004; revised 17 December 2004; accepted 20 December 2004
Abstract—The chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH-2), also found on eosinophils and
basophils, is a prostaglandin D2 receptor involved in the recruitment of these cell types during an inflammatory response. In this
report, we describe the synthesis and optimization of a ramatroban isostere that is a selective and potent antagonist of CRTH-2
which may be useful in the treatment of certain diseases.
Ó 2004 Elsevier Ltd. All rights reserved.
Asthma is a chronic inflammatory disease of the air-
ways. It is characterized by bronchial hyperresponsive-
ness, chronic pulmonary eosinophilia, and increased
lung mucus production. The inflammation associated
with asthma is characterized by an infiltration of many
cell types, including but not limited to mast cells, eosino-
phils, T-lymphocytes, monocytes, and neutrophils.1
These cells, along with their mediators, form a complex
cascade of interactions, which ultimately result in
inflammation of the airways.2 The preferred treatment
of asthma includes the use of anti-inflammatory agents
(such as corticosteroids or leukotriene inhibitors) and
bronchodilators (b2 adrenoceptor agonists). The
increasing prevalence of asthma and the variable re-
sponse to these agents indicate the need for novel treat-
ments involving different mechanisms and approaches.
released by activated mast cells and is greatly increased
in the bronchiolar lavage fluid of asthmatics.6 PGD2
signals through two G-protein coupled receptors
(GPCRs) from distinct GPCR subfamilies: PGD2 recep-
tor (DP), a prostanoid receptor7 and chemoattractant
receptor-homologous molecule expressed on TH2 cells8,9
(CRTH-2), a receptor that is most closely related to
receptors for ÔclassicalÕ chemoattractants, such as N-for-
myl peptide (FMLP), C3a, and C5a.10 CRTH-2 is
expressed in several tissues but has been most carefully
studied on TH2 cells, eosinophils, and basophils where
it appears to mediate the chemoattractant effect of
PGD2 on each of these cell types.8 In addition, PGD2
can induce eosinophil degranulation via CRTH-2 stimu-
lation.11 Taken together, these findings suggest an
involvement of PGD2 and CRTH-2 in asthma and per-
haps other inflammatory diseases.
Leukotrienes, prostaglandins, and thromboxanes are a
series of arachidonic acid metabolites known to exert a
variety of physiological functions that are mediated
through their respective receptors.3–5 Prostaglandin D2
(PGD2) is one of the major inflammatory molecules
Ramatroban (BAY u3405, 1) has been marketed in
Japan for allergic rhinitis as a selective thromboxane-
type prostanoid receptor (TP) antagonist (Fig. 1). How-
ever, recently ramatroban was also identified as a
CRTH-2 antagonist.12 As an entry into SAR studies
based on diverse leads generated from an internal HTS
campaign, this finding prompted us to explore the
hCRTH-2 pharmacophore by simply reversing the ram-
atroban backbone (Fig. 1, 2).
Keywords: CRTH-2; Prostaglandin D2; Ramatroban; Asthma.
*
Corresponding author. Tel.: +1 2164319900; fax: +1 2163619596;
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.12.055