Novel small molecule bradykinin B2 receptor antagonists.
Blockade of the bradykinin B(2) receptor provides therapeutic benefit in hereditary angioedema (HAE) and potentially in many other diseases. Herein, we describe the development of highly potent B(2) receptor antagonists with a molecular weight of approximately 500 g/mol. First, known quinoline-based B(2) receptor antagonists were stripped down to their shared core motif 53, which turned out to be the minimum pharmacophore. Targeted modifications of 53 resulted in the highly water-soluble lead compound 8a. Extensive exploration of its structure-activity relationship resulted in a series of highly potent B(2) receptor antagonists, featuring a hydrogen bond accepting functionality, which presumably interacts with the side chain of Asn-107 of the B(2) receptor. Optimization of the microsomal stability and cytochrome P450 inhibition eventually led to the discovery of the highly potent and orally available B(2) receptor antagonist 52e (JSM10292), which showed the best overall properties.
Gibson
Christoph
C
Department of Medicinal Chemistry, Jerini AG, Berlin D-10115, Germany. christoph.gibson@jerini.com
Schnatbaum
Karsten
K
Pfeifer
Jochen R
JR
Locardi
Elsa
E
Paschke
Matthias
M
Reimer
Ulf
U
Richter
Uwe
U
Scharn
Dirk
D
Faussner
Alexander
A
Tradler
Thomas
T
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D065094:Bradykinin B2 Receptor Antagonists; D002460:Cell Line; D015195:Drug Design; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D008970:Molecular Weight; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D013329:Structure-Activity Relationship
D065094:Bradykinin B2 Receptor Antagonists; D006571:Heterocyclic Compounds; D011804:Quinolines; D043782:Receptor, Bradykinin B2; C037219:quinoline