Novel Small Molecule Bradykinin B2 Receptor Antagonists

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4370 J. Med. Chem. 2009, 52, 4370–4379 DOI: 10.1021/jm9002445

Novel Small Molecule Bradykinin B2 Receptor Antagonists )

Christoph Gibson,*,† Karsten Schnatbaum,† Jochen R. Pfeifer,† Elsa Locardi,† Matthias Paschke,‡ Ulf Reimer,§ Uwe Richter,§ Dirk Scharn, Alexander Faussner,^ and Thomas Tradler‡ Jerini AG, Department of Medicinal Chemistry, Invalidenstrasse 130, Berlin, D-10115 Germany, ‡Jerini AG, Department of Lead Discovery Biology, Invalidenstrasse 130, Berlin, D-10115 Germany, §Jerini AG, Department of Computational Chemistry, Invalidenstrasse 130, Berlin, D-10115 Germany, Jerini AG, Department of DMPK & Analytics, Invalidenstrasse 130, Berlin, D-10115 Germany, and ^Ludwig-MaximiliansUniverstat Munchen, Abteilung fur Klinische Chemie und Klinische Biochemie, Nussbaumstrasse 20, D-80336 Munchen, Germany )

†

Received February 26, 2009

Blockade of the bradykinin B2 receptor provides therapeutic benefit in hereditary angioedema (HAE) and potentially in many other diseases. Herein, we describe the development of highly potent B2 receptor antagonists with a molecular weight of approximately 500 g/mol. First, known quinoline-based B2 receptor antagonists were stripped down to their shared core motif 53, which turned out to be the minimum pharmacophore. Targeted modifications of 53 resulted in the highly water-soluble lead compound 8a. Extensive exploration of its structure-activity relationship resulted in a series of highly potent B2 receptor antagonists, featuring a hydrogen bond accepting functionality, which presumably interacts with the side chain of Asn-107 of the B2 receptor. Optimization of the microsomal stability and cytochrome P450 inhibition eventually led to the discovery of the highly potent and orally available B2 receptor antagonist 52e (JSM10292), which showed the best overall properties.

Introduction a

The kinins bradykinin (BK; H-Arg-Pro-Pro-Gly-Phe-SerPro-Phe-Arg-OH) and kallidin (KD; H-Lys-Arg-Pro-ProGly-Phe-Ser-Pro-Phe-Arg-OH) are oligopeptide hormones generated as short-lived components of the kallikrein-kinin system. The concentration of circulating kinins is maintained at a low level under normal physiological conditions and may be rapidly increased under pathological situations by the enzymatic degradation of the circulating glycoprotein precursors called kininogens. The two most potent kininogenmetabolizing enzymes are the trypsin-like serine proteases plasma kallikrein and tissue kallikrein. The precursors of these enzymes are normally present in all tissues and are ready to be activated by physiological or pathophysiological processes.1 Two cell surface receptors, B1 and B2, have been classified, which mediate the cellular actions of kinins.2 Both receptors are members of the seven transmembrane G-protein-coupled receptor (GPCR) superfamily.3 They were characterized as endogenous and recombinant receptors in pharmacological studies as well as by generation of knockout mice.1c,4 B2 receptors are expressed constitutively in most cell and tissue types and mediate most of the known effects of BK and KD when these are produced in plasma or tissues.2a In contrast to the B2 subtype, B1 receptors are expressed at very low basal levels under physiological conditions and their expression is upregulated after exposure to proinflammatory or noxious stimuli.5 A large number of in vivo studies have *To whom correspondence should be addressed. Phone: þ49-30-9 78 93-281. fax: þ49-30-9 78 93-105. E-mail: [email protected]. a Abbreviations: BK, bradykinin; CAM, calcium mobilization; CYP, cytochrome P450; GPCR, G-protein-coupled receptor; IC50, inhibition constant for 50% inhibition; KD, kallidin; RLB, radio ligand binding; SAR, structure-activity relationship.

pubs.acs.org/jmc

Published on Web 06/24/2009

shown that the blockade of the B2 receptor may provide therapeutic benefit in pathological conditions such as asthma,6 allergic rhinitis,6b,7 pancreatitis,8 osteoarthritis,9 traumatic brain injury,10 Alzheimer’s disease,11 and angioedema.12 However, for the sake of completeness, it should be mentioned that bradykinin as a compensatory vasodilator may also have a salutary effect in certain clinical situations.13 Recently, in clinical trials, the highly specific B2 receptor antagonist icatibant14 proved to be efficacious in treating acute attacks of hereditary angioedema and thus demonstrated the therapeutic potential of B2 receptor antagonists.15 Since 1985, a number of peptide B2 receptor antagonists have been described, with the marketed drug icatibant being the most prominent representative of this group. Since the early 1990s, the drug discovery programs of many pharmaceutical companies resulted in the development of a diverse set of nonpeptide B2 receptor antagonists.16 In particular, the pioneering work of Fujisawa Pharmaceutical provided early evidence for the druggability of the B2 receptor based on small molecules. They described, in a series of publications and patent applications, the transformation of a directed random screening hit into a novel class of potent nonpeptide B2 receptor antagonists, including the orally available FK3657 (1)17 (Figure 1). In the following years, numerous patent applications have been filed disclosing B2 receptor antagonists featuring the 8-benzyloxy-2-methyl-quinoline motif of compound 1. Representative structures of this class of compounds are shown in Figure 1. Hoechst AG described close analogues to compound 1 such as compound 2, however without disclosing the activity at the human B2 receptor.18 Anatibant (3), developed by Fournier, represents one of the most advanced small molecule B2 receptor antagonists, but no data have been published demonstrating oral availability of this compound.19 In January 2007, a phase II clinical trial for r 2009 American Chemical Society

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Scheme 1a

a

Reagents and conditions: (a) X = Br: heterocycle, n-BuLi, THF, -78 C, then ZnCl2, -40 C, then Pd2dba3, PPh3, 80 C; (b) X = Cl: heterocycle, dioxane, 100 C; (c) Pd(PPh3)4, Na2CO3, dioxane/H2O, 100 C; (d) 3,5-dichloro-4-chloromethyl-pyridine (15), Cs2CO3, DMF, rt; (e) bis(pinacolato)diborane, Pd(dppf)Cl2, KOAc, DMSO, 85 C.

Figure 1. Selected small molecule B2 receptor antagonists featuring the 8-benzyloxy-2-methyl-quinoline motif.

traumatic brain injury was initiated by Xytis using an injectable formulation of compound 3. Recently, Menarini described a series of highly polar B2 receptor antagonists including MEN16132 (4) dedicated for the treatment of airway inflammatory pathologies.20 These compounds were optimized for inhalation and show minimum systemic exposure after intratracheal administration. It is important to note that the average molecular weight of the disclosed B2 receptor antagonists is rather high. In fact, with a high molecular weight of 592.5 g/mol, compound 1 represents one of the smallest B2 receptor antagonist published to date. As a consequence, most of these compounds feature properties commonly considered as unfavorable with regards to oral bioavailability such as a high number of rotatable bonds and a large polar surface area. In this paper, we wish to document the development of highly potent B2 receptor antagonists with a molecular weight of approximately 500 g/

mol. The discovery of the minimal pharmacophore, followed by extensive exploration of its structure-activity relationship (SAR) resulted in 52e (JSM10292), which proved to be a highly active B2 receptor antagonist being orally available in rat. Chemistry. The synthesis of 4-heteroaryl-substituted quinolines featuring a dichloro pyridine core is depicted in Scheme 1. The five-membered heterocycles were either coupled as zincates to the 4-bromo quinoline 5b via Negishi couplings (method a) or condensated with the 4-chloro quinoline 5a (method b). The halogen substituted five-membered heterocycles were coupled with boronic acid 7 via Suzuki couplings (method c). When necessary, the heterocycles were employed protected by suitable protecting groups and deprotected after the coupling to the quinoline. Scheme 2 shows the synthesis of compounds with various substituents in 3-position of the pyridine core. All syntheses started from 10 or 11. The halogen atom of these building blocks or analogues made out of them were substituted via a variety of different reactions: nucleophilic displacement by oxygen (method d) or sulfur (method q or p), Heck reaction (method g), or halogen-metal exchange followed by formylation (method i, Scheme 2). Further transformations with standard methodology afforded compounds 38a-q. Compounds containing a 4-methyl pyridine core structure were synthesized according to Scheme 3. Carbonylation of 4-bromo-2-chloro-pyridine, selective methylation at the bromine position, and subsequent standard transformations afforded the benzylic chlorides 44, 47, and 48. Different heterocycles were coupled to the 4-bromo quinoline core via Negishi coupling methodology. Alkylation with the previously synthesized benzylic chlorides yielded the desired compounds 52a-e. Results and Discussion We decided to start our program with the exploration of established quinoline-based B2 receptor antagonists, as ex-

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Scheme 2a

a

Reagents and conditions: (a) NaBH4, EtOH, rt; (b) 3,4-dihydro-2H-pyran, pTsOH, DCM, rt; (c) SOCl2, catalytic quantity of H2O, DCM, rt; (d) KOtBu, dioxane, 100 C; (e) ClCH2CON(CH3)2, Cs2CO3, THF, rt; (f) 6h, Cs2CO3, DMF, rt; (g) CH2dCHCONH2 or CH2dCHCON(CH3)2, Pd(OAc)2, DIEA, P(oTol)3, DMF, 120 C; (h) NaBH4, MeOH, rt; (i) n-BuLi, ethylformate, -78 C f rt; (j) Ac2O, pyridine, rt or dimethylcarbamoyl chloride, NaH, DMF, rt; (k) MsCl, NEt3, DCM, 0 C; (l) pyridone, Cs2CO3, DMF, rt; (m) DPPA, DBU, toluene, rt; (n) H2, Pd/C, MeOH, rt; (o) Cl-COR6, aq NaHCO3, DCM, rt; (p) thiazole-2-thiol or 1-methyl-1H-imidazole-2-thiol, Cs2CO3, THF, rt; (q) NaSH, DMF, rt; (r) BrCH2CONH2 or ClCH2CONMe2, NaHCO3, DMF, rt; (s) H2O2, HOAc, 50 C; (t) MsCl, Et3N, DCM, rt.

emplified in Figure 1. It was obvious, however, that the druglike properties of this class of antagonists were compromised by their high molecular weight. Consequently, we were focusing on the discovery of key pharmacophores that may ultimately result in the design of downsized and highly active B2 receptor antagonists. The implementation of this strategy is outlined in Figure 2. First, the quinoline-based B2 receptor antagonists were stripped down to their shared core motif 53, which turned out to be the minimum pharmacophore. Compound 53 showed acceptable affinity to the B2 receptor as determined in the radio ligand binding (RLB) assay, but due to poor aqueous solubility of less than 1 μM, 53 was of

limited use as a lead compound. Inspired by the work of Sawada et al., who showed that the activity of quinoline-based B2 receptor antagonists can be improved by the introduction of a five-membered heterocycle in the 4-postion of the quinoline moiety,21 we decided to substitute 53 with a polar imidazole ring in the corresponding position. In addition, the phenyl ring was replaced by a pyridine ring, resulting in the substantially more polar 8a. Because of its good aqueous solubility of >50 μM, low molecular weight of 385 g/mol, and respectable respectrable IC50 value of 580 nM in the RLB assay, compound 8a was selected as the lead compound for further modifications. Optimization of the five-membered

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Scheme 3a

Figure 2. Outline of the optimization program resulting in the highly active and orally available B2 receptor antagonist 52e.

Reagents and conditions: (a) LDA, THF, -78 C, then methylchloroformate, -78 C; (b) ZnMe2, Pd(dppf)Cl2, dioxane, 70 C; (c) CuCN, NMP, 180 C; (d) DIBAL, AlCl3, THF, -95 C f 4 C; (e) isobutyryl chloride, CH2Cl2, aq Na2CO3, rt; (f) SOCl2, CH2Cl2, rt; (g) DIBAL, THF, -78 C f rt; (h) 3,4-dihydro-2H-pyran, pTsOH, DCM, rt; (i) vinyl boronic acid anhydride pyridine complex, K2CO3, Pd(PPh3)4, DME/H2O, 100 C; (j) O3, DCM, -50 C, 10 min, then NaBH4, MeOH, -50 C f rt; (k) MsCl, NEt3, DCM, 0 C; (l) 3-trifluoromethylpyridin-2-ol, Cs2CO3, DMF, rt; (m) Li, naphthalene, ZnCl2, THF, -78 C f -40 C, then 4-bromo-8-(tert-butyl-dimethyl-silanyloxy)-2methyl-quinoline, Pd(PPh3)4, 70 C; (n) TBAF, THF, rt; (o) n-BuLi, ZnCl2, THF, -78 C f -40 C, then 4-bromo-2-methyl-quinolin-8-ol, Pd2dba3, PPh3, THF, 80 C; (p) Cs2CO3, DMF, rt. a

heterocycle and subsequent exploration of pyridine substituents resulted in a series of highly potent B2 receptor antagonists such as the thiazolyl-thioether 38b, which benefits from the formation of a hydrogen bond between its thiazole ring and the side chain of Asn-107 of the B2 receptor (see below for a detailed discussion of the Asn-107 interaction). The discovery of this specific interaction eventually enabled the development of the highly potent low molecular weight B2 receptor antagonist 52e. First, we were focusing on the optimization of the fivemembered heterocycle of lead compound 8a, which is shown in Table 1. The in vitro activity was assessed in both a RLB

assay based on specific binding of [3H]-BK to recombinant human B2 receptor expressed in HEK293 cells and a BKmediated calcium mobilization (CAM) assay using HF-15 primary human fibroblasts. We discovered that the modest binding affinity of the quinoline 9 could be improved by a factor of up to 265 by the installation of an appropriate fivemembered heterocycle in the 4 position of the quinoline moiety. A diverse set of unsubstituted heterocycles proved to be tolerated by the B2 receptor such as the N-linked imidazole ring (8a), the N-linked (8f) and the C3-linked (8g) pyrazole ring as well as the thiazole ring (8m, 8n, and 8q). The imidazole derivatives 8a-8e revealed the general SAR of the five-membered heterocycles. The introduction of a methyl group adjacent to the quinoline moiety (8b, 8d) usually improved the binding affinity, while those antagonists featuring an N-atom acceptor opposite to the methyl and quinoline group (8c) lost appreciable affinity. An additional substituent was tolerated vicinal to the methyl group (8e), although it slightly negatively impacted the affinity. Installation of a pyrazole ring (8f-8j) generally led to compounds with enhanced functional potency as compared to the imidazole derivatives (8a-8e), and it was not unexpected that the methylation of the N-atom of 8g adjacent to the quinoline moiety resulted in an improved binding affinity (8h). The C-methylated pyrazole 8i revealed a substantially higher binding affinity than the C-methylated pyrazole 8j, indicating that the preferred tautomeric forms correlate with the structures shown in Table 1. Hence 8i features an N-H opposite to the methyl and quinoline group, resulting in a beneficial effect on the binding affinity, whereas 8j features an N-atom acceptor in this position resulting in an unfavorable receptor interaction. This general trend was also observed in the triazole series in which the methylated triazole 8k exhibited high binding affinity, while shifting one N-atom to the critical position (8l) was again not tolerated by the B2 receptor. Regarding the binding affinity to the B2 receptor, the preferred attachment

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Table 1. SAR of Five-Membered Heterocycle: Binding Affinity and Functional Activity of Compounds 9 and 8a-w on the B2 Receptora

a Values represent the numerical average of at least two experiments. b IC50 of specific binding of [3H]-BK to recombinant human B2 receptor expressed in HEK293 cells. c IC50 of BK-mediated calcium mobilization in HF-15 primary human fibroblasts.

point for the unsubstituted thiazole ring (8m, 8n, and 8q) was shown to be the 4C-position. In the case of both the 5C-linked thiazole derivative (8o) and the 4C-linked thiazole derivative (8r), the introduction of a methyl group adjacent to the quinoline moiety only slightly improved the binding affinity. Replacement of the methyl group with a chlorine atom resulted in an approximate 9-fold loss in affinity of the 5Clinked derivative (8p) and an approximate 3-fold loss in affinity of the 4C-linked derivative (8s). Two methylated isothiazole derivatives were found to show decent (8t) to excellent (8u) binding affinity. However, replacement of the sulfur atom of the thiazole and isothiazole rings with an oxygen atom was not tolerated by the B2 receptor, as was shown by the oxazole 8v and isoxazole 8w. Because B2 antagonists with N-linked five-membered heterocycles proved to be moderately unstable under acidic conditions due to hydrolysis of the five-membered heterocycle-quinoline bond, we decided to abandon further exploration of these compounds. Because of their good binding affinity and good functional potency as well as due to their superior liver microsomal stability, the N-methyl pyrazole derivatives (8h) and 4C-methyl pyrazole derivatives (8i) were chosen for further modifications. Although the chloro-thiazole 8s revealed only moderate functional potency, it was also

selected because preliminary metabolite identification studies revealed that its chloro-thiazole ring was highly resistant to microsomal degradation. After the optimization of the five-membered heterocycle, we directed our attention to the exploration of the pyridine SAR. The corresponding phenyl cores of all previously reported quinoline-based B2 receptor antagonists are characterized by a large substituent in the meta position to the quinolinyloxymethyl moiety (Figure 1). We hypothesized that the structural diversity found in this position indicates a lack of specific receptor interaction that may preclude the development of a small meta substituent with high binding affinity. As a result, we decided to explore the alternative ortho position based on the easily accessible N-methyl pyrazole derivatives. The results of our efforts are shown in Table 2. In the lower nanomolar range, the test compound concentration equals the B2 receptor concentration of the RLB assay. This results in a limitation of the validity of the corresponding IC50 values. With a B2 receptor concentration in the picomolar range, we considered the CAM assay more reliable for the evaluation of highly potent antagonists. Furthermore, in contrast to the RLB assay, the CAM assay proved to be sensitive enough to monitor ligand-mediated activation of endogenous B2 receptors in human HF-15 foreskin fibroblasts. The ability to

Article Table 2. Binding Affinity and Functional Activity of Compounds 8h and 38a-q on the B2 Receptora

a Values represent the numerical average of at least two experiments. IC50 of specific binding of [3H]-BK to recombinant human B2 receptor expressed in HEK293 cells. c IC50 of BK-mediated calcium mobilization in HF-15 primary human fibroblasts. b

measure endogenous B2 receptors seems particularly attractive for the generation of SAR and the selection of a drug candidate, as it enables to employ the B2 receptor in its native environment. Thus, at this stage of the project, we decided to have the optimization of the potent advanced lead compounds guided by the CAM assay. Because all tested compounds were isolated as colorless solids, they are not likely to cause nonspecific optical interactions in the CAM assay. Substitution of the hydrogen atom with a chlorine atom in ortho position to the quinolinyloxymethyl moiety of 38a improved the activity by a factor of 10 (8h), presumably due to a hydrophobic interaction with the B2 receptor. The

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synthesis and evaluation of an ortho thioether library revealed that the installation of a hydrogen bond accepting functionality such as a thiazole (38b) or an imidazole ring (38c) led to an enhanced functional potency. In the 4-imidazol-1-yl-quinoline series (data not shown), the thiazol-2-yl-thioether derivative proved to be 9-fold more potent than the thiophene-2-yl-thioether analogue, which lacks the hydrogen bond acceptor. Modeling studies involving the generation of homology model ensembles for the B2 receptor and extensive docking and optimization efforts could rationalize these findings, suggesting the formation of a hydrogen bond between the side chain of asparagine 107 and the thiazole ring of 38b. The calculated binding model was supported by sitedirected mutagenesis experiments with the 4-imidazol-1-ylquinoline analogue of compound 38b. This compound competed for the [3H]-BK binding site at the wild type B2 receptor with an IC50 value of 470 nM and with an IC50 value of 2300 nM at the N107A mutant. To eliminate the metabolically labile and potentially cytochrome P450 (CYP)-inhibiting thioether-linked heterocycles, a number of alternative hydrogen bond accepting functionalities were evaluated. It turned out that replacement of the thioether-linked heterocycle with an appropriate thioetherlinked amide fragment maintained the functional potency (38d). Mere replacement of the thioether group with a sulfoxide (38e), an ether (38f), or a methylene group (38g) resulted in a significantly reduced functional potency. Compound 38h, however, demonstrated with an excellent IC50 value of 2.3 nM in the CAM assay that the combination of sulfur-methylene exchange and nitrogen atom shift of the amide group leads to an improved in vitro activity. Transformation of the amide group of 38h into a urea group (38i) did not alter the functional potency, whereas the corresponding carbamate 38j proved to be less potent. A general trend observed for compounds in this series was that hydrophobic substituents vicinal to the carbonyl group substantially improved functional potency in the CAM assay while barely affecting binding affinity in the RLB assay. This is exemplified by the acetamide 38l, which was 10-fold less potent in the CAM assay when compared to the isopropyl amide 38h. In this series, it was shown that the replacement of the amide group with an ester (38m) or sulfonamide group (38n) resulted in a significant reduced functional potency. We ultimately discovered that the potency could be maintained by replacing the amide group with a nitrogen-linked pyridone ring (38o), whose functional potency could be further improved by the installation of a CF3-group in ortho position to the carbonyl group (38q). With a number of highly active B2 receptor antagonists in hand, we focused on the optimization of microsomal stability and CYP inhibition. In a series of structurally related analogues of the compounds shown in Table 2, we observed that shifting the nitrogen atom of the pyridine core in para position to the chlorine atom positively impacted both microsomal stability and CYP inhibition. However, para-chloro-pyridine derivatives are usually prone to nucleophilic substitution reactions, and we observed a substantial improvement of the water solubility by switching from the chlorine to the methyl group, which prompted us to choose the para-methyl pyridine analogues for further optimization (Table 3). The SAR of the para-methyl-pyridine derivatives proved to be fairly consistent with that of the meta-chloro-pyridine derivatives. Excellent potency was achieved by installation of a hydrophobic moiety adjacent to the carbonyl group as exemplified by the N-methyl pyrazole analogues 52a, 52b, and

4376 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 14 Table 3. Binding Affinity and Functional Activity of Compounds 52a-e on the B2 Receptora

a Values represent the numerical average of at least two experiments. IC50 of specific binding of [3H]-BK to recombinant human B2 receptor expressed in HEK293 cells. c IC50 of BK-mediated calcium mobilization in HF-15 primary human fibroblasts. b

52c. The trifluoromethyl-substituted pyridone 52c revealed the highest potency as well as the highest human microsomal stability in this series. Preliminary metabolite identification studies based on the incubation with liver microsomes identified the N-methyl pyrazole group as a major metabolic soft spot, which turned out to be prone to metabolic demethylation. We therefore decided to discontinue further exploration of N-methylated five-membered heterocyle analogues. Good microsomal stability and high potency was eventually achieved by the combination of the CF3-pyridone-substituted framework with a chloro-thiazole ring (52d) or a C-methyl pyrazole ring (52e). With 34% remaining parent compound after 30 min incubation in the liver microsome assay, the chloro-thiazole analogue 52d proved to be slightly superior to the C-methyl pyrazole analogue 52e, which showed 21% remaining of parent compound in the same assay. However, in contrast to 52e, 52d was found to be a potent inhibitor of CYP2C19 (IC50 = 0.3 μM), which caused us to select 52e for a more comprehensive profiling. Compound 52e displayed neutral antagonist activity in the CAM assay and featured no partial agonistic activity up to the highest tested concentration of 5 μM. Preliminary pharmacokinetic studies in female Wistar rats showed that 52e features low clearance (CL = 21 mL/(min 3 kg), good terminal half-life (67 min), and substantial oral bioavailability (F > 17%).22 Conclusions In this study, we demonstrated the feasibility of the development of highly potent quinoline-based B2 receptor antagonists featuring a low molecular weight of approximately 500 g/ mol. By systematic downsizing of known B2 antagonists, we identified the minimum pharmacophore 53, which was used as the starting point for our extensive SAR studies. The installation of a hydrogen bond accepting functionality at the pyridine ring enabled a significant enhancement of the functional potency with only minor increase in molecular weight. In this series, the highly potent and orally available B2 antagonist 52e revealed the best overall properties. Further characterization and complete pharmacological profile of 52e will be published shortly.

Gibson et al.

Experimental Section Chemistry (General). All commercially available solvents and reagents were used without further treatment as received unless otherwise noted. All reactions were stirred magnetically; moisturesensitive reactions were performed under argon in heatgundried glassware. For analytical TLC, Merck silica gel 60 F254 plates were used and column chromatography was performed on Merck silica gel 60 (0.015-0.040 mm). All tested compounds were analyzed by HPLC-MS on a Surveyor HPLC combined with an LCQ classic or Advantage (all Thermo Electron, US) equipped with an ESI-source and showed a purity of >95%. 1H NMR spectra were measured in ACN-D3, CDCl3, or DMSOd6 with a Varian 500 MHz spectrometer; chemical shifts are expressed in ppm relative to TMS as internal standard and coupling constants (J) in Hz. Synthesis of 3,5-Dichloro-4-chloromethyl-pyridine (15). NaBH4 (0.838 g, 22.2 mmol) was added to a stirred solution of 3,5-dichloro-pyridine-4-carbaldehyde (3.0 g, 17 mmol) in ethanol (40 mL). After stirring for 35 min at room temperature, the reaction mixture was concentrated in vacuo, and the residue was redissolved in ethyl acetate (200 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give (3,5-dichloro-pyridin-4-yl)methanol (2.83 g, 94%), which was used in the next step without purification. MS (m/z): 178.1 [M þ Hþ]. SOCl2 (2.3 mL, 32 mmol) was added dropwise to a stirred solution of (3,5-dichloro-pyridin-4-yl)-methanol (2.83 g, 15.9 mmol) in DCM (20 mL) over 10 min. After stirring for 35 min at room temperature, saturated aqueous Na2CO3 solution (40 mL), and DCM (60 mL) was added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with EA/hexane 1:4) to give the title compound (15) (2.65 g, 85%). MS (m/z): 196.0 [M þ Hþ]. Synthesis of 8-(3,5-Dichloro-pyridin-4-ylmethoxy)-2-methylquinoline (9). Cs2CO3 (261 mg, 0.8 mmol) was added to a vigorously stirred solution of 3,5-dichloro-4-chloromethyl-pyridine (15) (48 mg, 0.24 mmol) and 2-methyl-quinolin-8-ol (32 mg, 0.2 mmol) in DMF (1 mL). After stirring for 18 h at room temperature, the solvent was removed in vacuo. The residue was purified by reversed phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound (280 mg, 65%) as the TFA salt. 1H NMR (500 MHz, ACN-d3): δ = 8.66 (d, J = 8.1 Hz, 1H), 8.43 (s, 2H), 7.79 (t, J =Hz, 1H), 7.757.61 (m, 3H), 5.47 (s, 2H), 2.80 (s, 2H). MS (m/z): 319.0 [M þ Hþ]. Synthesis of 2-Methyl-4-(1-methyl-1H-imidazol-2-yl)-quinolin-8-ol (6d). n-Butyllithium (1.6 M in hexane, 6.0 mL, 9.7 mmol) was added dropwise to a stirred solution of 1-methyl-1Himidazole (0.83 mL, 11 mmol) in anhydrous THF (60 mL) at -87 C. The reaction mixture was allowed to warm to -40 C. A solution of ZnCl2 (3.9 g, 28 mmol) in anhydrous THF (28 mL) was than added dropwise at -78 C. The reaction mixture was allowed to reach room temperature and was than transferred to a suspension of Pd(PPh4)4 (340 mg, 0.29 mmol) and 4-bromo-2methyl-quinolin-8-ol (5b) (1.0 g, 4.2 mmol) in anhydrous dioxane (20 mL). After stirring for 90 min at 80 C, the reaction mixture was cooled to room temperature, MeOH (5 mL) was added, and the solvent was removed in vacuo. The residue was partitioned between DCM (150 mL) and water (50 mL). The pH of the aqueous layer was adjusted to 11 by the addition of concentrated aqueous NH3 solution, and the aqueous layer was extracted with DCM (2  100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/MeOH 20:1) to give the title compound 6d (614 mg, 61%). 1H NMR (500 MHz, DMSO-d6): δ = 7.53 (s, 1H), 7.42 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 1.5 Hz, 1H), 7.09 (dd, J = 7.3, 1.5 Hz, 1H), 3.58 (s, 3H), 2.75 (s, 3H). MS (m/z): 240.2 [M þ Hþ].

Article

Synthesis of 8-(3,5-Dichloro-pyridin-4-ylmethoxy)-2-methyl4-(1-methyl-1H-imidazol-2-yl)-quinoline (8d). Quinoline 6d (16 mg, 67 μmol) was reacted with 3,5-dichloro-4-chloromethyl-pyridine (13 mg, 67 μmol) (15) as described for the synthesis of 9. Purification by reversed phase HPLC using a gradient of acetonitrile in water with 0.1% TFA yielded the title compound 8d (6.9 mg, 20%) as a TFA salt. MS (m/z): 399.2 [M þ Hþ]. 1H NMR (DMSO-d6): δ = 8.79 (s, 2H), 7.97 (s, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 5.52 (s, 2H), 3.70 (s, 3H), 2.72 (s, 3H). Synthesis of 8-(3,5-Dichloro-pyridin-4-ylmethoxy)-2-methyl4-(4-methyl-2H-pyrazol-3-yl)-quinoline (8i). 4-Methyl-1H-pyrazole (0.8 mL, 9.94 mmol) was dissolved in 4 mL DMF, and BOM-Cl (1.5 mL, content of 60%, 5.0 mmol) was added at 0 C. The reaction mixture was stirred for 45 min at rt and then was quenched with 1 mL of aq NH3. The solvents were removed in vacuo, and the residue was partitioned between water and DCM and extracted with DCM (3  20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/methanol 20:1) gave 1-benzyloxymethyl-4-methyl-1H-pyrazole (1.36 g, 68%). 1H NMR (DMSO-d6): δ = 7.67 (s, 1H), 7.37-7.26 (m, 6H), 5.42 (s, 2H), 4.48 (s, 2H). MS (m/z): 203.0 [M þ Hþ]. 1-Benzyloxymethyl-4-methyl-1H-pyrazole (191 mg, 0.95 mmol) was coupled with 4-bromo-2-methyl-quinolin-8-ol (5b) (75 mg, 0.32 mmol) according to the procedure described for the synthesis of 6d. Purification by flash chromatography on silica gel (elution with DCM/EtOAc 20:1) gave the BOMprotected quinoline derivative 6i (99.8 mg, 87%). MS (m/z): 360.3 [MþHþ]. Quinoline 6i (47 mg, 131 μmol) was reacted with 3,5-dichloro4-chloromethyl-pyridine (15) (28 mg, 146 μmol) as described for the synthesis of 9. Purification by reversed phase HPLC using a gradient of acetonitrile in water with 0.1% TFA yielded the BOM-protected title compound (5.5 mg, 5%) as a TFA salt. MS (m/z): 399.2 [M þ Hþ]. This compound (5.5 mg, 6.4 μmol) was dissolved in a mixture of 1.4 mL of TFA and 150 μL of DCM. The reaction mixture was stirred at 80 C for 2 h and concentrated in vacuo. Purification by reversed phase HPLC using a gradient of acetonitrile in water with 0.1% TFA yielded the title compound 8i (2.1 mg, 44%) as the TFA salt. 1H NMR (DMSOd6): δ 8.78 (s, 2H), 7.80-7.42 (m, 5H), 5.52 (s, 2H), 2.71 (br s, 3H), 2.01 (br s, 3H). MS (m/z): 399.1 [M þ Hþ]. Synthesis of [4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)pyridin-2-yl]-methanol (43). Pyridine carboxylic ester 41 (300 mg, 1.62 mmol) was dissolved in THF (3 mL) and cooled to -78 C before DIBAL-H (1.5 M in toluene, 3.2 mL, 4.86 mmol) was added dropwise. The reaction mixture was allowed to warm to -20 C over a period of 2 h. DIBAL-H (1.1 mL, 1.62 mmol) was added and stirring was continued for 16 h (-20 C to rt). The reaction mixture was then quenched by the addition of water (0.30 mL) at -20 C. ACN (22 mL) and concentrated aqueous NH3 (1.8 mL) was added to the mixture. After vigorous stirring for 30 min, the suspension was centrifuged and the precipitate suspended in a solution of ACN (6.5 mL) and concentrated aqueous NH3 (0.8 mL). After vigorous stirring for 30 min, the suspension was centrifuged. The combined supernatants were concentrated in vacuo to give the alcohol (2-chloro-4-methyl-pyridin-3-yl)-methanol (266 mg, 104%), which was used in the next step without further purification. MS (m/z): 158.1 [M þ Hþ]. Alcohol (2-chloro-4-methyl-pyridin-3-yl)-methanol (266 mg, 1.62 mmol) was dissolved in DCM (10 mL) and 3,4-dihydro-2Hpyran (0.22 mL, 2.4 mmol) and para-toluene sulfonic acid (0.37 g, 1.9 mmol) were added and the reaction mixture was stirred for 1 h at rt. After removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel with DCM/EtOAc (40:1 f 30:1 f 20:1) to provide the pyridine derivative 42 (276 mg, 71%). MS (m/z): 242.0 [M þ Hþ].

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A solution of chloro-pyridine 42 (500 mg, 2.07 mmol), vinyl boronic acid anhydride pyridine complex (498 mg, 2.07 mmol), K2CO3 (286 mg, 2.07 mmol) in DME (16.5 mL), and water (7 mL) was deoxygenated before Pd(PPh3)4 (120 mg, 0.10 mmol) was added. The reaction was heated to 100 C and stirred at this temperature for 20 h, cooled to rt, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EtOAc 6:1 f 4:1) to give 4-methyl-3(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine (432 mg, 89%). MS (m/z): 195.0 GC/MS [Mþ]. A solution of vinyl pyridine 4-methyl-3-(tetrahydro-pyran-2yloxymethyl)-2-vinyl-pyridine (300 mg, 1.29 mmol) in DCM (36 mL) was cooled to -50 C, and a stream of ozone was bubbled through it until the color of the reaction mixture changed to light blue. Sodium borohydride (486 mg, 12.9 mmol) was suspended in MeOH (15 mL) and immediately added to the ozonide solution. The reaction mixture was warmed to room temperature (1 h). After checking that all ozonides had been destroyed by means of iodine starch paper, solvents were removed in vacuo. The residue was partioned between water and DCM was extracted with CH2Cl2 (3  20 mL). The organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (elution with DCM/MeOH 40:1 f 20:1) delivered the alcohol 43 (254 mg, 1.23 mmol, 83%). MS (m/z): 476.0 [M þ Hþ]. Synthesis of 1-(3-Chloromethyl-4-methyl-pyridin-2-ylmethyl)3-trifluoromethyl-1H-pyridin-2-one (44). Alcohol 43 (36 mg, 0.15 mmol) and NEt3 (63 μL, 0.45 mmol) were dissolved in THF (1 mL), and methanesulfonyl chloride (13 μL, 0.17 mmol) was added. The reaction mixture was stirred for 10 min at rt before the solvents were removed in vacuo. The residue was dissolved in DMF (0.35 mL) and added dropwise to a stirred suspension of 3-trifluoromethyl-pyridin-2-ol (24 mg, 0.15 mmol) and Cs2CO3 (49 mg, 0.15 mmol) in DMF (0.40 mL). After stirring for 2 h at rt, sat. NaHCO3 (2 mL) was added. The mixture was extracted with DCM (2  10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (elution with hexane/EtOAc 2:1 f 1:1) yielded 1-[4-methyl-3-(tetrahydropyran-2-yloxymethyl)-pyridin-2-ylmethyl]-3-trifluoromethyl-1Hpyridin-2-one (21 mg, 37%). MS (m/z): 382.8 [M þ Hþ]. 1-[4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2ylmethyl]-3-trifluoromethyl-1H-pyridin-2-one (21 mg, 54.9 μmol) could be directly converted into the chloride 44 according to the procedure described for the synthesis of 15, and it was used in the next step without further purification. MS (m/z): 317.1 [M þ Hþ]. Synthesis of 1-{4-Methyl-3-[2-methyl-4-(4-methyl-2H-pyrazol3-yl)-quinolin-8-yloxymethyl]-pyridin-2-ylmethyl}-3-trifluoromethyl1H-pyridin-2-one (52e). 4-Methyl-1H-pyrazole (550 mg, 6.7 mmol) was dried by coevacuation with toluene. Pyridinium p-toluenesulfonate (168 mg, 0.67 mmol), DCM (30 mL), and 3,4-dihydro-2Hpyran (1.82 mL, 20.1 mmol) were added and the reaction stirred at 55 C for 16 h. After concentration in vacuo, the residue was purified by flash chromatography on silica gel using a gradient of hexane and EtOAc to give 49 (1.09 g, 98%). MS (m/z): 166.8 [M þ Hþ]. 2-Methyl-4-[4-methyl-2-(tetrahydro-pyran-2-yl)-2H-pyrazol3-yl]-quinolin-8-ol (6i) was prepared from 4-bromo-2-methylquinolin-8-ol (302 mg, 1.277 mmol) and pyrazole 49 (530 mg, 3.20 mmol) according to the procedure described for the synthesis of 6d. Purification by flash chromatography on silica gel (elution with DCM/methanol 20:1) gave the quinoline derivative 6i (392 mg, 95%). MS (m/z): 324.0 [M þ Hþ]. Chloride 44 (1.00 g, 3.16 mmol) was reacted with quinoline 6i (1.12 g, 3.48 mmol) as described for the synthesis of 9. Purification by flash chromatography on silica gel (elution with DCM/ MeOH 20:1 f 10:1) delivered 54 (2.02 g, 106%). MS (m/z): 604.2 [M þ Hþ]. Quinoline 54 (2.02 g, 3.34 mmol) was dissolved in MeOH (25 mL) and concentrated aq HCl (2.5 mL) was added. After

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stirring for 30 min, the solvents were removed in vacuo and the residue was purified by reversed phase HPLC using a gradient of acetonitrile in water with 0.1% TFA to give the title compound 52e (1.16 g, 40%) as the TFA salt. 1H NMR (500 MHz, DMSOd6): δ 8.42 (d, J = 5.0 Hz, 1H), 8.13 (dd, J = 6.6, 1.6 Hz, 1H), 8.11-7.81 (m, 4H), 7.36 (d, J = 5.0 Hz, 1H), 6.43 (t, J = 7.2 Hz, 1H), 5.69 (s, 2H), 5.47 (s, 2H), 2.96 (br. s, 3H), 2.53 (s, 3H), 2.14 (s, 3H). MS (m/z): 520.1 [M þ Hþ].

Acknowledgment. We thank Lena von Oertzen, Dagmar Riexinger, Rocco Weise, Stephanie Koepke, Katy Pesta, Nicole Liebelt, Bianka Knopp, Daniela Wulf, Daniel Herrmann, Nadine Muller, and Maren Schlief for technical assistance. HF15 human primary fibroblast cells were kindly provided by Prof. Dr. Roscher (University Hospital of Munich).

Gibson et al.

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Supporting Information Available: Experimental procedures, characterization of new compounds, radioligand binding assay, calcium mobilization assay, PK studies (general), microsomal stability assay, CYP inhibition assay, and details of molecular modeling. This material is available free of charge via the Internet at http://pubs.acs.org.

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work. Improvement of aqueous solubility and new insights into species difference. J. Med. Chem. 2004, 47, 1617–1630. (22) %F is based on AUCall. A substantial amount of 52e was detected in the last obtained plasma sample (480 min), which means that the actual oral bioavailability is significantly higher than 17%.