Cholecystokinins (CCKs) act as anti-opioid peptides. CCK was initially described as a regulatory hormone found in endocrine cells of the gastro-intestinal (GI) tract. Some CCKs share a common amino acid sequence with gastrin, which is involved in control of gastric acid and pepsin secretion. CCKs have also been found throughout the central nervous system (CNS), where they act as neurotransmitter and/or modulator of many important functions. There are various known structures of CCK, identified with reference to the number of amino acids they comprise. For example, CCK-8 a naturally-occurring predominant CCK peptide having only eight amino acids, is the minimum fully-active sequence. Albeit, small amounts of CCK-4 have also been reported.
CCKs have multiple function in the physiology and pathology of vertebrate. Pharmaceuticals and biotechs have taken advantage of the pathological properties of the CCKs to develop molecules that block these properties to deliver health and wellness. For instance, CCK plays an important role in the invasiveness and the production of matrix metalloproteinase-9 (MMP-9) in human pancreatic cancer cell lines. The pathway of the invasiveness may be associated with MMP-9 of those lines regulated by CCK.
The gut hormone CCK exerts various actions on the gastrointestinal tract, including the regulation of growth. The hormone has been reported to induce hypertrophy and hyperplasia of the pancreas and to enhance chemically-induced pancreatic carcinogenesis in animals. Stimulation of endogenous CCK secretion through the induction of deficiency of intraintestinal proteases and bile salts by trypsin-inhibiting nutrients, bile salt-binding drugs or surgical intervention is also capable of stimulating growth and tumour development in the rat. In humans, factors suggested to increase the risk of pancreatic cancer, such as a high-fat- and high-protein-diet or gastrectomy, are known to stimulate plasma CCK secretion. Receptors for CCK have been demonstrated in human pancreatic adenocarcinomas, and CCK has been demonstrated to enhance the pancreatic xenograft growth and growth of gastric and bile duct cancer.
The actions of CCK are mediated by two G protein coupled receptor (GPCRs). They are termed as type-A and type-B, reflecting their preferential localisation in the alimentary tract and in the brain, respectively. Recently, these receptors have been re-named as CCK1 and CCK2, respectively, although the original designation is also used hereinbelow with respect to the present invention. The molecular cloning of two CCK receptor subtypes, one from rat and human pancreas and one from human brain, has confirmed the pharmacological classification of the CCK receptors. The differential distribution of CCK1 and CCK2 receptors in the peripheral vs. central nervous system is not absolute, as CCK1 receptors have also been shown to be expressed in discrete regions of the CNS, including the spinal cord, particularly in primates.
The functions of the CCK1 receptor in the brain are poorly understood, whereas the CCK2 receptor is known to mediate anxiety, panic attacks, satiety and pain. Therefore, antagonists to CCK receptors and to gastrin have been useful to prevent and treat CCK-related and/or gastrin-related disorders. Just as there are some overlap in the biological activities of CCK and gastrin, antagonists also tend to have affinity for both receptors.
Selective CCK receptor antagonists are themselves useful in treating CCK-related disorders of the appetite regulatory systems as well as in potentiating and prolonging opiate-mediated analgesia, thus having utility in the treatment of pain, while selective gastrin antagonists are useful in the modulation of CNS behaviour, as a palliative for gastrointestinal neoplasms, and in the treatment and prevention of gastrin-related disorders of the GI system in humans and animals, such as peptic ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia and other conditions in which reduced gastrin activity is of therapeutic value. Also, since CCK and gastrin also have trophic effects on certain tumours, antagonists of CCK and gastrin are useful in treating these tumours.
Various chemical classes of CCK-receptor antagonists have been reported. These include pyrazolidinones showing good selectivity for CCKB receptors (Howbert, J. J. et. al.; Bioorg. Med. Chem. Lett. 1993, 3, 875-880.), ureidoacetamides which are potent and selective ligands for CCKB/gastrin receptors (WO 91/113874), ureidophenoxyacetanilides (Takeda, Y. et. al.; Chem. Pharm Bull. 1998, 46, 951-961), ureidomethylcarbamoylphenylketones (Hagishita, S.; et. al., Bioorg. Med. Chem. 1997, 5, 1695-1714), and ureidobenzodiazepine derivatives (Evans, B. E.; et. al., Proc. Natl. Acad. Sci. USA 1986, 83, 4918-4922).