Ben E. Evans

Progress in the development of oxytocin antagonists for use in preterm labor.

From a targeted screening effort and medicinal chemistry program, L-368,899 was selected as the first orally-active oxytocin (OT) antagonist to enter clinical trials. In animal studies, L-368,899 was shown to be a potent and selective OT antagonist and was orally bioavailable in rats, dogs and chimpanzees. L-368,899 was further shown to be a potent OT antagonist in pregnant rhesus and to inhibit spontaneous nocturnal uterine contractions. In Phase I human studies, L-368,899 was generally well-tolerated given intravenously and showed significant plasma levels after oral administration. In addition, L-368,899 blocked OT-stimulated uterine activity in postpartum women with a potency similar to that in the pregnant rhesus monkey. More recently, another structural series has been pursued, represented by L-371,257 [1-(1-(4-(N-acetyl-4-piperidinyloxy)-2-methoxybenzoyl)pip eridin-4-yl)- 1,2-dihydro-4(H)-3,1-benzoxazin-2-one]. L-371,257 exhibits high affinity (Ki, 4.6 nM) for human uterine OT receptors with high selectivity vs. human vasopressin receptors. In rat tissues in vitro, L-371,257 is a potent and competitive OT antagonist (pA2, 8.4) and, in vivo, blocks OT-stimulated uterine activity given both i.v. and intraduodenally. L-371,257 highlights the promise of this novel structural class.

An expedient synthesis of 3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

Abstract Racemic 3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 2, was prepared in four steps utilizing a novel mercuric ion assisted ammonia displacement of an N-acyl alkylthioglycine amide 5 .

A new amine resolution method and its application to 3-aminobenzodiazepines

Abstract A new method for the resolution of amines and its application to 3-aminobenzodiazepines 1 is described. The method involves the synthesis and separation of a pair of phenylalanyl amide diastereomers followed by removal of phenylalanine via the Edman degradation to give the individual enantiomers of 1 with high chiral purities.

Design of cholecystokinin peptidomimetics

Abstract Cholecystokinin (CCK) is a polypeptide hormone which occurs in numerous molecular forms at various sites throughout the peripheral and central nervous systems. The wide range of physiological responses which have been attributed to CCK has stimulated the search for agents which mimic or block its action. Two principal CCK receptor subtypes have been characterized and numerous peptide substrate analogues have been identified which bind potently with these receptor subtypes. However, a number of insufficiencies inherent in peptide structures have limited their application as drugs. These shortcomings include rapid breakdown to inactive substances by proteases, poor transport, and rapid excretion. Such properties limit the duration of action and bioavailability of peptides and have prompted researchers to initiate the development of compounds which have less peptide character, indeed, to develop totally nonpeptidal agents. We describe the discovery of several potent non-peptide CCK antagonists which display selectivity versus the peripheral (CCK-A) and central (CCK-B) receptors. The most thoroughly characterized of these agents are the benzodiazepine derivatives MK-329 and L-365,260. These novel CCK antagonists are orally effective, long acting and devoid of agonist activity. MK-329 and L-365,260 should find widespread use in delineating the function of CCK receptors in human physiology and may have potential clinical application.