title: Development of human calcitonin gene-related peptide (CGRP) receptor antagonists. 1. Potent and selective small molecule CGRP antagonists. 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-l-lysyl]-4-(4-pyridinyl)piperazine: the first CGRP antagonist for clinical trials in acute migraine.
abstract: Although the triptans have greatly improved the acute treatment of migraine headache, there are yet many shortcomings. Therefore, new strategies for the treatment of migraine are needed which offer advantages over current therapy, e.g. triptans. Our novel approach was based on the hypothesis that the release of calcitonin gene-related peptide (CGRP) could play a causative role in migraine headache. Thus we initiated a program aimed at the design and synthesis of small molecule CGRP receptor antagonists. High throughput screening led to the identification of (R)-Tyr-(S)-Lys dipeptide-like compounds that showed weak but unequivocal binding to the human CGRP receptor. Lead optimization afforded highly potent CGRP antagonists, the prototype being compound 19 (BIBN4096). This compound exhibiting a favorable biological profile was selected for initial clinical trials. A proof of concept study indicated that intravenous application of 19 was effective in the treatment of acute migraine headache. This finding strongly supports our initial working hypothesis that CGRP plays an important role in the pathophysiology of migraine.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Research Division, Birkendorfer Strasse 65, 88397 Biberach/RISS, Germany. klaus.rudolf@bc.boehringer-ingelheim.com
authors.forename: Klaus
authors.initials: K
authors.lastname: Rudolf
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eberlein
authors.forename: Wolfhard
authors.initials: W
authors.lastname: Engel
authors.forename: Helmut
authors.initials: H
authors.lastname: Pieper
authors.forename: Michael
authors.initials: M
authors.lastname: Entzeroth
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hallermayer
authors.forename: Henri
authors.initials: H
authors.lastname: Doods
mesh_terms: D000208:Acute Disease; D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002144:Callithrix; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000096:biosynthesis; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008881:Migraine Disorders / Q000188:drug therapy*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013154:Spleen / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C505165:1-(N(2)-(3,4-dibromo-N-((4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl)carbonyl)tyrosyl)lysyl)-4-(4-pyridinyl)piperazine; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004151:Dipeptides; D011799:Quinazolines; D000242:Cyclic AMP