Parallel solid-phase synthesis of disubstituted (5-biphenyltetrazolyl) hydantoins and thiohydantoins targeting the growth hormone secretagogue receptor.
An efficient solid-phase protocol for the synthesis of substituted (5-biphenyltetrazolyl)-hydantoins and -thiohydantoins has been developed. Suzuki cross-coupling between resin-bound 2-(tetrazol-5-yl)-phenylborinane and 4-bromobenzaldehyde gave the corresponding tetrazolylbiphenyl aldehyde. Subsequent reductive amination using amino acid esters gave the pivotal resin bound amino acid esters which were transformed to hydantoins or thiohydantoins via two routes: (i) treatment with isocyanates or isothiocyanates or (ii) successive treatment with triphosgene and primary amines. Using molecular modeling, we were able to jump from L-692,429, a well known non-peptidyl growth hormone secretagogue (GHS), to biphenyltetrazolyl hydantoins, obtaining compounds with IC(50) values below 600 nM after two iterative cycles only.
Severinsen
Rune
R
Medicinal Chemistry, Novo Nordisk A/S, Novo-Nordisk Park 2760, Maaloev, Denmark.
Lau
Jesper F
JF
Bondensgaard
Kent
K
Hansen
Birgit S
BS
Begtrup
Mikael
M
Ankersen
Michael
M
D016503:Drug Delivery Systems / Q000379:methods*; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000378:metabolism; D008958:Models, Molecular; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D054440:Receptors, Ghrelin; D011986:Receptors, Somatotropin / Q000378:metabolism; D013867:Thiohydantoins / Q000138:chemical synthesis* / Q000378:metabolism
D006827:Hydantoins; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D011986:Receptors, Somatotropin; D013867:Thiohydantoins; D019382:Human Growth Hormone