Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 1. Synthesis and SAR of alpha,alpha-dimethylglycine sulfonamides.
We recently published the extensive in vivo pharmacological characterization of MEN 16132 (J. Pharmacol. Exp. Ther. 2005, 616-623; Eur. J. Pharmacol. 2005, 528, 7), a member of the sulfonamide-containing human B(2) receptor (hB(2)R) antagonists. Here we report, in detail, how this family of compounds was designed, synthesized, and optimized to provide a group of products with subnanomolar affinity for the hB(2)R and high in vivo potency after topical administration to the respiratory tract. The series was designed on the basis of indications from the X-ray structures of the key structural motifs A and B present in known antagonists and is characterized by the presence of an alpha,alpha-dialkyl amino acid. The first lead (17) of the series was submitted to extensive chemical work to elucidate the structural requirements to increase hB(2) receptor affinity and antagonist potency in bioassays expressing the human B(2) receptor (hB(2)R). The following structural features were selected: a 2,4-dimethylquinoline moiety and a piperazine linker acylated with a basic amino acid. The representative lead compound 68 inhibited the specific binding of [(3)H]BK to hB(2)R with a pKi of 9.4 and antagonized the BK-induced inositolphosphate (IP) accumulation in recombinant cell systems expressing the hB(2)R with a pA(2) of 9.1. Moreover, compound 68 when administered (300 nmol/kg) intratracheally in the anesthetized guinea pig, was able to significantly inhibit BK-induced bronchoconstriction for up to 120 min after its administration, while having a lower and shorter lasting effect on hypotension.
Fattori
Daniela
D
Menarini Ricerche, Via Tito Speri 10, 00040 Pomezia, Roma, Italy.
Rossi
Cristina
C
Fincham
Christopher I
CI
Berettoni
Marco
M
Calvani
Federico
F
Catrambone
Fernando
F
Felicetti
Patrizia
P
Gensini
Martina
M
Terracciano
Rosa
R
Altamura
Maria
M
Bressan
Alessandro
A
Giuliani
Sandro
S
Maggi
Carlo A
CA
Meini
Stefania
S
Valenti
Claudio
C
Quartara
Laura
L
D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D065094:Bradykinin B2 Receptor Antagonists; D016085:Bronchoconstrictor Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007295:Inositol Phosphates / Q000096:biosynthesis; D008958:Models, Molecular; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
D001920:Bradykinin; D065094:Bradykinin B2 Receptor Antagonists; D016085:Bronchoconstrictor Agents; D007295:Inositol Phosphates; D000077489:Piperazine; D010879:Piperazines; D011804:Quinolines; D043782:Receptor, Bradykinin B2; D012521:Sarcosine; D013449:Sulfonamides; C512075:N-(2-(4-(2-amino-5-(dimethylamino)pentanoyl)piperazin-1-yl)-1,1-dimethyl-2-oxoethyl)-2,3-dichloro-3-(2,4-dimethylquinolin-8-yloxymethyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C025138:dimethylglycine