Kelly P. Longo

Preparation and radiolabelling of CP-96,345, the first non-peptide substance P antagonist

Abstract The preparation of CP-96,345, a potent, non-peptide Substance P antagonist, in both enantiomerically pure and radiolabelled forms is described. In addition, the absolute configuration of CP-96,345 was determined to be 2S,3S.

Nuclear variations of quinuclidine substance P antagonists: 2-diphenylmethyl-1-azabicyclo[3.2.2]nonan-3-amines

Abstract The synthesis and SAR of a series of 1-azabicyclo[3.2.2] analogues of the nonpeptide substance P antagonist CP-96,345 are described. The results demonstrate the sensitivity of the substance P receptor toward alterations in the nuclear structure of CP-96,345.

UK-73,093: A non-peptide neurotensin receptor antagonist

Abstract UK-73,093 was identified in a screening program as a compound able to displace [ 3 H]-neurotensin from its bovine brain receptor. We describe the discovery of this compound, species differences in receptor affinity and its characterization as a functional neurotensin antogonist in vitro and in vivo .

Discovery of CP-96,345 and its characterization in disease models involving substance P.

Studies with CP-96,345, a potent, selective, orally active, nonpeptide NK1 receptor antagonist, have provided considerable insight into SP pharmacology. Rather than being a primary neurotransmitter, SP prolongs the nociception produced by other neurotransmitters. By controlling endothelial permeability, SP plays a major role in inflammation and inflammatory aspects of asthma, possibly by regulating the access of neutrophils to an inflammatory site. These results indicate potential therapeutic applications for SP antagonists in the treatment of chronic pain, inflammation, and inflammatory aspects of asthma, and signal a new era in the clinical management of these important diseases.

2-Aryl-1-azabicyclo[2.2.2]octanes as novel nonpeptide substance P antagonists

Abstract The synthesis and SAR of a series of 2-aryl-1-azabicyclo[2.2.2]octanes structurally related to the nonpeptide substance P antagonists CP-96,345 and CP-99,994 are described. The novel SAR observed at the 2-position in these derivatives represents a hybrid between that seen in the two previous series.