The design, synthesis, and biological activity of a series of high-affinity, basic ligands for the cholecystokinin-B receptor are described. The compounds, which incorporate a piperidin-2-yl or a homopiperidin-2-yl group attached to C-5 of a benzodiazepine core structure, are substantially more basic (e.g., 9d, pK(a)=9.48) than previously reported antagonists based on 5-amino-1,4-benzodiazepines (e.g., 5, pK(a)=7.1) and have improved aqueous solubility. In view of their basicity, it would be tempting to speculate that the present series of compounds might be binding to the CCK-B receptor in their protonated form. Compounds such as 9d,e and 10d showed high affinity for this receptor (IC50 < 2.5 nM) and very good selectivity over CCK-A (CCK-A/CCK-B > 2000), even as the racemates. Additionally, a significantly improved in vivo half-life was observed for a selection of compounds compared to the clinical candidate L-365,-260 (1).

The design, synthesis, and biological activity of a novel series of CCK-B receptor antagonists (1) which incorporate a tetrazol-5-ylamino functionality attached to the phenyl ring of the arylurea moiety of L-365,260 are described. In these compounds, the acidity of the tetrazole was gradually modified by utilization of simple conformational constraints, and X-ray crystallographic data were obtained to support the conformational depenence of the pK(a) of the aminotetrazoles. Compounds to emerge from the present work such as 1f and 2c,d are among the highest affinity and, in the case of 1f, most selective (CCK-A/CCK-B, 37 000) antagonists so far reported for this receptor. The C(5)-cyclohexyl compound 2c (L-736,380) dose-dependently inhibited gastric acid secretion in anesthetized rats (ID(50), 0.064 mg/kg) and ex vivo binding of [(125)I]CCK-8S in BKTO mice brain membranes (ED(50), 1.7 mg/kg) and is one of the most potent acidic CCK-B receptor antagonists yet described.

A novel series of potent, water-soluble benzodiazepine based CCKB/gastrin antagonists has been prepared which incorporate an N-methylpiperazine group at the C5 position of the benzodiazepine ring system. The N1-n-propyl analogue (7b) is a high affinity, selective and potent receptor antagonist in vitro, with good bioavailability and excellent oral absorption providing high plasma levels in vivo.

Acylsulphonamide analogues of the meta-tolylurea L-708,474 have been synthesised and evaluated as CCKB receptor antagonists. Such derivatives retain very high affinity and subtype selectivity for the CCKB receptor, and have good aqueous solubility. The ortho-tolyl acylsulphonamide L-736,309 is orally bioavailable and brain penetrant in rat.

The novel 3-ureidobenzazepin-2-ones 11 and 12, which incorporate a cationic substituent at the 5-position were designed and synthesised as ligands for the CCKB receptor. These compounds proved to have high affinity for the CCKB receptor and were selective over the CCKA receptor subtype. This work further defines the role of the benzazepine template as a bioisostere for the 1,4-benzodiazepine template of earlier CCK antagonists.

The C5-cyclohexyl analogue of the cholecystokinin type-B (CCKB) receptor antagonist L-365,260 has been prepared. This derivative has significantly higher CCKB affinity and markedly improved CCKB/CCKA receptor selectivity (6,500 v. 87-fold) than the parent compound. It is one of the most potent and selective CCKB ligands reported to date.