Reflections on some pilot trials of gastrin receptor blockade in pancreatic cancer.

The experience of synthesising a novel gastrin receptor antagonist gastrazole and taking it into 3 small clinical studies in pancreatic cancer in man is described. The need for such a compound is illustrated by the observation that inhibition of gastric acid secretion by H2 receptor antagonists results in hypergastrinaemia. A large number of cell types have gastrin receptors including pancreatic cancer cells which have been shown to be stimulated by gastrin. Small numbers of pancreatic cancer patients given gastrazole by continuous intravenous infusion showed prolonged survival compared with best supportive care or placebo, and equivalent survival to those given 5 fluouracil. The results suggest a greater benefit for patients with early stage disease. An alternative gastrin receptor antagonist YF 476 is also described which has the advantage of efficacy given by the oral route. This new compound requires to be studied in pancreatic cancer and other diseases associated with hypergastrinaemia.

Optimization of 1,3,4-benzotriazepine-based CCK(2) antagonists to obtain potent, orally active inhibitors of gastrin-mediated gastric acid secretion.

Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of [125I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- [1,2,4]oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration.

Optimization of the in vitro and in vivo properties of a novel series of 2,4,5-trisubstituted imidazoles as potent cholecystokinin-2 (CCK2) antagonists.

The systematic optimization of the structure of a novel 2,4,5-trisubstituted imidazole-based cholecystokinin-2 (CCK(2)) receptor antagonist afforded analogues with nanomolar receptor affinity. These compounds were now comparable in their potency to the bicyclic heteroaromatic-based compounds 5 (JB93182) and 6 (JB95008), from which the initial examples were designed using a field-point based molecular modeling approach. They were also orally active as judged by their inhibition of pentagastrin stimulated acid secretion in conscious dogs, in contrast to the bicyclic heteroaromatic-based compounds, which were ineffective because of biliary elimination. Increasing the hydrophilicity through replacement of a particular methylene group with an ether oxygen, as in 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]amino}benzoic acid (53), had little effect on the receptor affinity but significantly increased the oral potency. Comparison of the plasma pharmacokinetics and the inhibition of pentagastrin-stimulated acid output following bolus intraduodenal administration of both 53 and 6 indicated that 53 was well absorbed, had a longer half-life, and was not subject to the elimination pathways of the earlier series.

Gastrin agonists and antagonists.

This review generally describes work in the area of CCK2 or gastrin receptor agonists and antagonists before focussing on highlights of studies in these areas carried out at the James Black Foundation over the last dozen years. Thus, an alanine scan of BOC-tetragastrin coupled with a bioassay in the isolated mouse stomach led to new insights as to the nature of the function of the various residues of the peptide. This in turn produced molecules such as the peptoid, JB 90118 which was an antagonist in all in vitro systems explored but was found to be CCK1 selective and an agonist still in vivo. We then go on to describe attempts to mimic a putative 3(10) helical conformation for BOC-tetragastrin which had been suggested by fluorescence studies. Structures based on the dibenzobicylo[2.2.2]octane skeleton appeared to fulfil the requirements of the pharmacophore and promising initial results were obtained after the requisite molecules were synthesised. Optimisation of this series led to compounds with affinities in the nanomolar range but which were lacking in consistency when examined in vivo. Further manipulation, this time of the skeleton, led to molecules such as JB 93182 which were of equivalent affinity but with a better profile of action in vivo. It was found during exploration of the SAR of this new series that even relatively small alterations to the structure could give rise to molecules which behaved as agonists. Attempts to improve the oral bioavailability of JB 93182 by reduction of its molecular weight were aided by a molecular modelling approach which ultimately gave rise to another new series, some imidazole derivatives, exemplified by JB 98248.