bx-471 and Multiple-Sclerosis

Chemokines belong to a large family of chemoattractant molecules involved in the directed migration of immune cells. They achieve their cellular effects by direct interaction with cell surface receptors. The chemokine receptor CCR1 appears to be involved in a variety of proinflammatory and autoimmune diseases and this makes it a very attractive therapeutic target. This review discusses the identification, chemistry, biology and therapeutic potential of BX 471 a potent CCR1 antagonist that is currently in the clinic for a variety of indications.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Humans; Multiple Sclerosis; Phenylurea Compounds; Piperidines; Protein Serine-Threonine Kinases; Psoriasis

Berlex and its parent company, Schering AG, are developing BX-471 (also known as ZK-811752), the lead in a series of non-peptide chemokine receptor 1 (CCR1) antagonists, for the potential treatment of autoimmune diseases, in particular multiple sclerosis (MS) [291682], [376290], [411184]. In March 2000, BX-471 was undergoing phase I trials for the potential treatment of autoimmune diseases [362022]; phase I trials in MS were ongoing in March 2002 [441989], [443941]. Positive results from these trials have been reported and Berlex was planning phase II trials in MS patients as of mid-March 2002 [444906]. In July 2001, Schering estimated filing in the US and EU in 2008 [411184], [416493]. WO-09856771 claims piperazinyl derivatives, pharmaceutical compositions comprising them and their use in the treatment of inflammatory conditions.

Topics: Animals; Autoimmune Diseases; Clinical Trials, Phase I as Topic; Drug Evaluation, Preclinical; Graft Rejection; Humans; Multiple Sclerosis; Phenylurea Compounds; Piperidines; Receptors, CCR1; Receptors, Chemokine; Structure-Activity Relationship; Treatment Outcome

We assessed the safety and efficacy of orally administered CC chemokine receptor 1 (CCR1) antagonist in 105 patients with relapsing/remitting MS (RRMS) in a 16-week, randomized, double-blind, placebo-controlled trial. The primary endpoint was the cumulative number of newly active lesions on serial MRI scans. Other MRI, immunologic, and clinical outcomes were also explored. No significant treatment difference was observed for any tested MRI variable. CCR1 does not contribute to initial leukocyte infiltration in RRMS.

Topics: Central Nervous System; Chemokines; Chemotaxis, Leukocyte; Disease Progression; Double-Blind Method; Drug Administration Schedule; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Multiple Sclerosis; Phenylurea Compounds; Piperidines; Placebos; Receptors, CCR1; Receptors, Chemokine; Signal Transduction; Treatment Outcome