Graeme Semple

YF476 is a new potent and selective gastrin/cholecystokinin‐B receptor antagonist in vitro and in vivo

Background: We newly synthesized YF476 ((R)‐1‐[2,3‐dihydro‐2‐oxo‐1‐pivaloylmethyl‐5‐(2′‐pyridyl)‐1H‐1,4‐benzodiazepin‐3‐yl]‐3‐(3‐methylamino‐phenyl)urea) as a gastrin/cholecystokinin‐B (CCK‐B) receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo.

Peptidomimetic aminomethylene ketone inhibitors of interleukin-1β-converting enzyme (ICE)

Pyridone-based peptidomimetic inhibitors of recombinant human Interleukin-1 beta-converting enzyme (ICE, caspase-1) with an aminomethylene ketone activating group in the P1 position are described. Several analogues with sub-nanomolar Kis versus ICE and improved aqueous solubility are reported.

New Benzylureas as a Novel Series of Potent, Nonpeptidic Vasopressin V2 Receptor Agonists

Vasopressin (AVP) is a hormone that stimulates an increase in water permeability through activation of V2 receptors in the kidney. The analogue of AVP, desmopressin, has proven an effective drug for diseases where a reduction of urine output is desired. However, its peptidic nature limits its bioavailability. We report herein the discovery of potent, nonpeptidic, benzylurea derived agonists of the vasopressin V2 receptor. We describe substitutions on the benzyl group to give improvements in potency and subsequent modifications to the urea end group to provide improvements in solubility and increased oral efficacy in a rat model of diuresis. The lead compound 20e (VA106483) is reported for the first time and has been selected for clinical development.

PYRIDONE-BASED PEPTIDOMIMETIC INHIBITORS OF INTERLEUKIN-1β-CONVERTING ENZYME (ICE)

Abstract New potent, reversible inhibitors of recombinant human Interleukin-1β-converting enzyme (ICE, caspase-1) with significantly reduced peptide character are described. The compounds were designed by incorporation of pyridone and pyrimidone heterocyclic replacements for the P2-P3 amino acids of the native substrate and were optimised by manipulation of peripheral alkyl and aryl substituents.

Synthesis and biological activity of 1-alkylcarbonylmethyl analogues of YM022

Abstract A novel series of 1-alkylcarbonylmethyl analogues of the potent gastrin/CCK-B receptor antagonist YM022 have been prepared. A number of analogues retained good affinity for the gastrin/CCK-B receptor and one compound (6d) showed improved binding and enhanced selectivity for this receptor over CCK-A. A second compound (6j) gave improved in vivo inhibition of gastric acid secretion in rats. Both analogues were shown to have significantly better activity in the same model following i.d. dosing than either YM022 or L-365,260.

Synthesis and biological activity of 5-heteroaryl benzodiazepines: analogues of YM022

Abstract A novel series of analogues of the potent gastrin/CCK-B receptor antagonist YM022 have been prepared which incorporate 5- and 6-membered heteroaromatic rings in the benzodiazepine 5-position. The 5-(2-pyridyl) derivatives in particular retained good in vitro and in vivo potency and one such compound 9i was shown to inhibit acid secretion after oral dosing in dogs. Improved bioavailability for 9i over the 5-phenyl analogue, 9h was demonstrated in rats.

A facile large scale synthesis of optically active 3-amino-5-(2-pyridyl)-1,4-benzodiazepin-2-one derivatives

Abstract A facile method for the synthesis of 3-amino-5-(2-pyridyl)-1,4-benzodiazepin-2-ones (8) mediated by benzotriazole is described. The synthesis and optical resolution of the product by fractional crystallisation proceeds in high yield, under mild conditions and without recourse to toxic reagents or chromatographic separations and hence is amenable to the large scale preparation of these important precursors to potent CCK receptor ligands.

Cholecystokinin analogues: The ergopeptine alkaloids as models of the active conformation of CCK

Abstract Ergotamine was shown to inhibit the binding of radiolabelled CCK to both CCK-A and CCK-B receptors with a relatively modest potency (IC50 = 30 μM and 17 μM respectively).

Identification and biological activity of novel peptidomimetic gastrin/CCK-B receptor agonists

Abstract The design, synthesis and biological activity of two novel series of compounds derived from the basic Boc-CCK-4 structure which provide potent ligands for the gastrin/CCK-B receptor is outlined. Within these series, new pseudopeptide compounds were discovered which unexpectedly were functional agonists in vivo, as shown by their ability to stimulate basal gastric acid secretion in rats, an effect which was blocked by the potent gastrin/CCK-B receptor antagonist YM022.