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1 (Table 1).14 Because of the above-mentioned concerns, we started searching for a new P-CAB that has low lipophilicity, excellent ADME-Tox parameters like compound 2a, and moderately long duration of acid suppression (Fig. 1), on the basis of the hypothesis that com- pound 2a may show a little excessive duration of action in humans. Consequently, we succeeded in identifying a novel ?uoropyrrole derivative by further modi?cations. Herein we report exploration of compounds and identi?cation of a novel ?uoropyrrole derivative as a P-CAB with optimal dura- tion of action. 2. Chemistry Synthesis of several commercially unavailable 2-pyridyl sul- fonylation reagents was accomplished as shown in Scheme 1. Con- densation of commercially available 2-halopyridines

3 with benzyl thiol by means of a nucleophilic aromatic substitution reaction or a palladium coupling reaction yielded corresponding 2-benzylth- iopyridines 4. 6-MeO derivative 4h was obtained from compound 4b via a substitution reaction with sodium methoxide. Subsequent oxidation of

4 with N-chlorosuccinimide (NCS) afforded corre- sponding sulfonyl halides 5. Reaction products of 4a and 4d were too unstable to be isolated as sulfonyl chlorides;

therefore, they were isolated as stable sulfonyl ?uoride derivatives 5a and 5d after treatment with potassium ?uoride. Synthesis of several commercially unavailable sulfonylation reagents for 3-pyridyl derivatives was accomplished as shown in Scheme 2. Condensation of commercially available or prepared compounds

6 with benzyl mercaptan via a palladium coupling reaction gave corresponding 7. As for tri?ate derivative 6a, it was obtained from compound 6f under basic conditions with a good Table

1 A series of properties of lead compound

1 and previously optimized P-CAB 2a . N S O O H N Me N F F N S O O H N Me OMe

1 2a N Compound C log P Log D pKa In vitro H + ,K + -ATPase inhibitory activities (IC

50 , nM) In vivo Acid secretion in rats (1 mg/kg, iv,% inhibition) ATP content% control at

100 l M hERG% inhibition at

10 l M Rat cassette dosing a Concentrations (ng/mL or ng/g) and AUC (ng ? h/mL or ng ? h/g) in rat plasma and stomach after intravenous administration at a dose of 0.2 mg/kg (as free base) C 10min C 1h C 4h C 24h AUC plasma stomach plasma stomach plasma stomach plasma stomach plasma stomach

1 3.88 1.54 9.48

30 95 (22.1) b 89.1 17.2 361.4 7.3 387.7 2.9

244 0

0 56

3730 2a 1.45 0.04 8.54

49 98 100.2 39.8 51.5 602.2

15 752.1

0 628.6

0 130.5

54 10,277 a All values are averages of three rats. b ATP content at

30 l M (% control).

3448 H. Nishida et al. / Bioorganic &

Medicinal Chemistry

25 (2017) 3447C3460 yield. Subsequent oxidation of compounds

7 afforded compounds

8 in a manner similar to the approach described above. Synthesis of ?uoropyrrole derivatives

20 was accomplished by starting from commercially available 9, and the synthesis method is shown in Scheme 3. Initially, the introduction of a ?uorine group into the pyrrole ring at position

4 was performed by directly applying ?uorination reactions to several pyrrole intermediates, but these methods were not practical because the ?uorination reaction step poses many dif- ?cult problems such as a low yield and selectivity, the need for pre- cise column chromatography, and the use of an expensive ?uorination reagent. To solve these problems, we attempted to develop an effective method for synthesis of ?uoropyrrole deriva- tives without direct ?uorination of the pyrrole ring. As a result, we succeeded in the development of a novel method for synthesis of ?uoropyrroles, consisting of key reactions such as a nucleophilic reaction with the carbonyl group of a lactam using pyridyl lithium and a novel allyl rearrangement reaction (SN20 reaction) accompa- nied by desorption of the ?uorine group and double-bond transposition. As for the synthesis of compound 12, it was successfully achieved by a method similar to the one described in the litera- ture.15 Condensation of compound