The in silico construction of a PDGFRβ kinase homology model and ensuing medicinal chemistry guided by molecular modeling, led to the identification of potent, small molecule inhibitors of PDGFR. Subsequent exploration of structure-activity relationships (SAR) led to the incorporation of a constrained secondary amine to enhance selectivity. Further refinements led to the integration of a fluorine substituted piperidine, which resulted in significant reduction of P-glycoprotein (Pgp) mediated efflux and improved bioavailability. Compound 28 displayed oral exposure in rodents and had a pronounced effect in a pharmacokinetic-pharmacodynamic (PKPD) assay.

RATIONALE: Prostaglandin D2 (PGD2), is a potent prostanoid released during allergic/asthmatic responses. CRTH2 (aka DP2), a PDG2 receptor expressed on cells involved in allergic inflammation, mediates chemotaxis and mast cell-dependent activation of basophils, eosinophils and Th2 lymphocytes. Thus, CRTH2 antagonists may be useful in allergic diseases. METHODS: ARRY-005 and ARRY-006 are potent, selective, orally bioavailable, competitive antagonists of CRTH2 (IC50 <10 nM). Human blood or basophils from healthy and allergic subjects were used for flow cytometry and chemotaxis assays. Balb/c mice were sensitized to OVA then challenged days on 28-30 with inhaled OVA in the asthma studies monitoring airway hyperresponsiveness (AHR) and inflammation or challenged with intranasal OVA on days 28-33 in the AR studies monitoring respiratory frequency (RF) or nasal resistance (Rna). Inhibitors were administered orally 1hr before each challenge. NC/Nga mice were used in the AD studies. RESULTS: ARRY-005 inhibited PGD2-mediated chemotaxis of isolated basophils (IC50 1 nM) and in human blood inhibited PGD2-induced eosinophil shape change (IC50 180 nM) and CRTH2 receptor internalization (IC50 ∼200 nM). ARRY-005 (30 mg/kg QD) decreased AHR and reduced BAL eosinophil and lymphocyte accumulation. In the AR model, ARRY-005 (10 mg/kg QD) normalized early and late phase decreases in RF and prevented the increases in Rna in the late phase. In the AD model, ARRY-006 (30 mg/kg, QD) inhibited ear thickening, erythema, and pruritis. CONCLUSIONS: Selective CRTH2 antagonists, ARRY-005 and -006, are potent inhibitors of basophils and eosinophils in vitro and exhibited significant protective activities in models of three allergic diseases, supporting their advancement to clinical development.