BI-44370

Migraine afflicts approximately 11% of the population worldwide producing substantial disability, resulting in loss of productivity both at home and at the workplace. Calcitonin gene-related peptide (CGRP) is closely involved in the cascade of molecular events leading to migraine painful crisis.

Acute treatment of migraine is actually based on the use of triptans, class drug which presents a clear limitation due to its cardiovascular side effects. Gepants, a CGRP antagonist class, might offer a new non-vasoconstrictive approach in the acute treatment of migraine. Four chemically unrelated CGRP receptor (CGRP-R) antagonists (olcegepant, telcagepant, MK-3207 and BI 44370 TA) have displayed efficacy in the treatment of migraine.

When compared with triptans, gepants class showed a similar efficacy, moreover corresponding to the best published results for oral triptans. CGRP antagonists are in different phases of their development, and the treatment of migraine could be based on the use of gepants, as class of acute medications. However, CGRP-R antagonists clinical trials seem to be discouraging for their forthcoming use in clinical practice. New CGRP-R antagonists, such as BMS-927711 and BI 44370 TA, are in the pipeline and their developments will outline the future of this drug class.

The treatment of migraine was advanced dramatically with the introduction of triptans in the early 1990s. Despite the substantial improvement in the quality of life that triptans have brought to many migraineurs, a substantial cohort of patients remain highly disabled by attacks and need new therapeutic approaches, which ideally should be quick-acting, have no vasoconstrictor activity, and have a longer duration of action and be better tolerated than current therapies. The calcitonin gene-related peptide (CGRP) receptor antagonists (gepants)-olcegepant (BIBN 4096 BS), telcagepant (MK-0974), MK3207, and BI 44370 TA-are effective in treating acute migraine. They have no vasoconstrictive properties, fewer adverse effects, and may act longer than triptans. Their development has been complicated by liver toxicity issues when used as preventives. Results from studies with BI 44370 TA do not support broad concern about a class effect, and further studies are ongoing in this respect. Many experimental studies and clinical trials suggest that nitric oxide may have a role in the pathophysiology of migraine. Therefore, the inhibition of nitric oxide synthase (NOS) for the acute or prophylactic treatment of migraine offered a feasible approach; as inducible NOS (iNOS) is involved in several pain states, such as inflammatory pain, it appeared to be an attractive target. However, despite high selectivity and potency, the iNOS inhibitor GW274150 was not effective for acute treatment or prophylaxis of migraine, suggesting that iNOS is very unlikely to be a promising target.