Preclinical Candidate Optimization
Preclinical Candidate Optimization
Kostich W.,Bristol Myers Squibb |
Hamman .B.D.,Lexicon Pharmaceuticals Inc. |
Li Y.-W.,Bristol Myers Squibb |
Naidu S.,Bristol Myers Squibb |
And 65 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2016
To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of a2 adrenergic and opioid receptors. These studies showed that a2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to a2 adrenergic signaling, a pathway known to be antinociceptive in humans. Copyright © 2016 The Author(s).
Li J.,Metabolic Diseases Chemistry |
Kennedy L.J.,Metabolic Diseases Chemistry |
Shi Y.,Metabolic Diseases Chemistry |
Tao S.,Metabolic Diseases Chemistry |
And 43 more authors.
Journal of Medicinal Chemistry | Year: 2010
An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) α agonist, with an EC50 of 10 nM for human PPARα and -410-fold selectivity vs human PPAR- in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR-. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARα ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARα in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed. © 2010 American Chemical Society.
Qiao J.X.,P.O. Box 4000 |
Wang T.C.,P.O. Box 4000 |
Adam L.P.,Discovery Biology |
Chen A.Y.A.,Discovery Biology |
And 29 more authors.
Journal of Medicinal Chemistry | Year: 2015
Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies. © 2015 American Chemical Society.