Synthetic chemists catch their breath

Clinical candidate for asthma treatment on hold.

Six years of research on a clinical candidate for the treatment of asthma has come to an abrupt halt following a change in direction at the company where the project was under way. John Duncia and colleagues at Bristol-Myers Squibb (BMS), Princeton, US, began working on cell-receptor antagonists with putative therapeutic potential in 1998 and discovered a particularly active molecule - BMS-639623 - in 2000. The project no longer fits with the company’s plans, leaving Duncia hoping that work on the molecule, which he says has proven efficacious in a primate model of allergic inflammation, can be carried on by others.

The molecule blocks a receptor found on the surface of inflammatory blood cells called eosinophils. Eosinophils are attracted into the airways of patients with asthma when this receptor, CC chemokine receptor 3 (CCR3), binds to its ligand, eotaxin. Activated eosinophils release a host of inflammatory agents thought to cause the tissue damage held responsible for the symptoms of asthma.

Duncia’s team began looking for a molecule that would effectively block CCR3 by screening DuPont Pharmaceutical’s compound library. The lead compound that they found blocked receptor binding by 50 per cent (the IC50 score) at a concentration of about 1 mM - not sufficiently potent for a novel therapy.

The researchers discovered that a 3-benzylpiperidine moiety introduced greater selectivity for the CCR3 receptor. They then rigidised a propyl chain between the piperidine and a urea by substituting it with two substituents - a methyl group and a hydroxyl group. ’Those two groups work together to induce a preferred conformation in the propyl chain for increased binding and functional potency’, Duncia told Chemistry World. Finally, the team discovered that of all the functional groups and heterocycles they substituted on the terminal phenylurea, a tetrazole ring gave rise to optimal binding potency. ’This likely relates to the unusual distribution of electron density in the tetrazole ring,’ he suggests. This final structure, BMS-639623, has a significantly improved IC50 of 0.4 nM.

The antagonist has been tested in cynomolgus monkeys and proven effective at blocking allergen-induced recruitment of eosinophils to the lungs, reports Duncia. In addition, he claims, it could readily be synthesised on the kilo scale.

Duncia presented his findings to chemists attending a meeting on organic synthesis in Riga, Latvia (see Chemistry World, July 2004, p8), hoping to stimulate interest in taking on the work. BMS is now considering licensing BMS-639623 to another company for clinical development.

Bea Perks