Development of CXCR3 antagonists. Part 4: discovery of 2-amino-(4-tropinyl)quinolines.

The synthesis and biological evaluation of a novel series of 2-aminoquinoline substituted piperidines and tropanes incorporating a homotropene moiety is herein described. The series exhibits potent antagonism of the CXCR3 receptor and superior physicochemical properties. Compound 24d was found to be orally bioavailable, and PK/PD studies suggested it as a suitable tool for studying the role of CXCR3 in models of disease.

Development of CXCR3 antagonists. Part 3: Tropenyl and homotropenyl-piperidine urea derivatives.

The optimization of a series of 1-aryl-3-piperidinyl urea derivatives is described in which incorporation of tropenyl and homotropenyl moieties has led to significant improvements in activity and drug-like properties. Replacement of the central piperidine with an exo-tropanyl unit led to the identification of compound 15 which provides a combination of excellent potency against human and murine receptors, drug-like properties and pharmacokinetics, thus providing a valuable tool for the evaluation of CXCR3 antagonists in models of human disease.

Novel nucleotide triphosphates as potent P2Y2 agonists with enhanced stability over UTP.

The synthesis of a series of novel C-linked nucleotide triphosphates is reported. These exhibit excellent agonist potency and selectivity for the P2Y2 receptor with a number of examples having EC50 values below 10 nM. Representative compounds from the N-linked and C-linked series showed enhanced metabolic stability compared with that of the natural ligand UTP.

Novel nucleotide triphosphates as potent P2Y2 agonists.

The synthesis and P2Y2 activities of a novel series of nucleoside triphosphates are described. Many of these compounds were potent agonists of the P2Y2 receptor.