PDF《Bioorganic & Medicinal Chemistry》

2017 Elsevier Ltd. All rights reserved. Abbreviations: ADME-Tox, absorption, distribution, metabolism, excretion, and toxicity;

AUC, area under the curve;

BnSH, benzyl mercaptan;

Xantphos, 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene;

CYP2C19, hepatic cytochrome P450 2C19;

CYP3A4, hepatic cytochrome P450 3A4;

DBU, 1,8-diazabicyclo[5.4.0]undec- 7-ene;

DSC, differential scanning calorimetry;

DMB, 2,4-dimethoxybenzyl;

DMAP, 4-dimethylaminopyridine;

DMSO, dimethyl sulfoxide;

Boc2O, di-tert-butyl dicar- bonate;

DMPK, drug metabolism and pharmacokinetics;

ESI, electrospray ioniza- tion;

IC50, half-maximal inhibitory concentration;

HPLC, high-performance liquid chromatography;

HRMS, high-resolution mass spectrometry;

hERG, human ether- a-go-go-related gene;

iv, intravenous injection;

LC/MS/MS, liquid chromatography with tandem mass spectrometry;

LDA, lithium diisopropylamide;

mp, melting point;

MeO, methoxy;

NCS, N-chlorosuccinimide;

po, er os;

P-CAB, potassium- competitive acid blocker;

PPI, proton pump inhibitor;

Py, pyridyl;

rt, room temperature;

THF, tetrahydrofuran;

TG-DTA, thermogravimetrydifferential thermal analysis;

TLC, thin-layer chromatography. ? Corresponding author at: 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. E-mail address: haruyuki.nishida@takeda.com (H. Nishida). Bioorganic &

Medicinal Chemistry

25 (2017) 3447C3460 Contents lists available at ScienceDirect Bioorganic &

Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc gastric acid secretion in rats and Heidenhain pouch dogs.13 Judging by the ?nding that compound 2a inhibits histamine-stimulated gas- tric acid secretion by approximately 80% in Heidenhain pouch dogs even after

48 h of oral administration at a dose of 0.8 mg/kg, com- pound 2a was hypothesized to exert stronger and much longer inhi- bition in humans as compared to PPIs. Actually, it holds great promise as a new P-CAB with unusually long duration of action. On the other hand, there is a possibility that the duration of action of compound 2a in humans cannot be deduced from the ani- mal data, and we were slightly concerned about a risk of too long duration of action of compound 2a in humans. Therefore, with the aim to discover a novel excellent P-CAB that would perfectly over- come the limitations of PPIs, we started to study how to precisely control the duration of action of pyrrole compounds. Major factors affecting the duration of gastric acid suppression were found to be H+ ,K+ -ATPase inhibitory activity in vitro and in vivo, the pattern of distribution to the stomach, and effectiveness of elimination (clearance) from the stomach, but the contribution rates of such factors were estimated to depend on the overall physicochemical properties of a compound in question. Therefore, to understand the duration of gastric-acid-suppres- sive activity comprehensively, we decided to evaluate not only basic physicochemical properties such as lipophilicity, basicity, and membrane penetration, which should determine tissue distri- bution, but also the actual concentration in the stomach. Consequently, gastric and plasma concentration pro?les after intravenous administration of compound 2a were determined by means of cassette dosing experiment, and it turned out that this compound remains in the stomach at rather high concentrations after

24 h in spite of elimination from blood plasma. In addition, compound 2a showed signi?cantly more effective transfer to (and retention in) the stomach as compared to pyrrole lead com- pound