Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: optimising brain penetration.
The optimisation of molecular properties within a series of 2-amino dihydroquinazoline 5-HT5A/5-HT7 receptor ligands resulted in a significantly improved brain-to-plasma ratio, enhancing the pharmacological utility of these compounds. By modulating the lipophilicity and pKa, a 20-fold increase in brain-to-plasma ratio could be achieved, leading to micromolar brain concentrations after oral administration. The enantiomers of one representative of this series of improved compounds were separated, and the configuration of the eutomer was determined by X-ray crystallography.
Peters
Jens-Uwe
JU
Discovery Chemistry, Pharma Division, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland. jens-uwe.peters@roche.com
Lübbers
Thomas
T
Alanine
Alexander
A
Kolczewski
Sabine
S
Blasco
Francesca
F
Steward
Lucinda
L
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D006146:Guanidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D006146:Guanidines; D008024:Ligands; D011743:Pyrimidines; D011799:Quinazolines; D011985:Receptors, Serotonin; C078730:serotonin 5 receptor; C104425:serotonin 7 receptor; C030986:pyrimidine