title: Reduced cardiac side-effect potential by introduction of polar groups: discovery of NIBR-1282, an orally bioavailable CCR5 antagonist which is active in vivo.
abstract: Introduction of polar groups in a series of potent CCR5 antagonists which are very likely to adversely affect the conduction system in the heart led to the identification of NIBR-1282 which did not show adverse effects when tested in an isolated rabbit heart ex vivo model. Administration of NIBR-1282 in combination with a non-efficacious dose of CsA led to significant prolongation of kidney allograft survival in cynomolgus monkeys.
authors.affiliation: Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, CH-4002 Basel, Switzerland. gebhard.thoma@novartis.com
authors.forename: Gebhard
authors.initials: G
authors.lastname: Thoma
authors.forename: Christian
authors.initials: C
authors.lastname: Beerli
authors.forename: Marc
authors.initials: M
authors.lastname: Bigaud
authors.forename: Christian
authors.initials: C
authors.lastname: Bruns
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Cooke
authors.forename: Markus B
authors.initials: MB
authors.lastname: Streiff
authors.forename: Hans-Guenter
authors.initials: HG
authors.lastname: Zerwes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells / Q000187:drug effects; D018938:Caco-2 Cells / Q000187:drug effects; D054405:Chemokine CCL3 / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D016572:Cyclosporine / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006085:Graft Survival; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation; D008252:Macaca fascicularis; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats
chemical_list: C515429:CCL3 protein, human; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D065607:Cytochrome P-450 Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D007166:Immunosuppressive Agents; C496884:KCNH1 protein, human; C529333:NIBR-1282; D011725:Pyridines; D016572:Cyclosporine