title: The design and preparation of metabolically protected new arylpiperazine 5-HT1A ligands.
abstract: New arylpiperazines related to buspirone, gepirone and NAN-190 were designed and screened in silico for their 5-HT(1A) affinity and potential sites of metabolism by human cytochrome p450 (CYP3A4). Modifications to these structures were assessed in silico for their influence on both 5HT(1A) affinity and metabolism. Selected new molecules were synthesized and purified in a parallel chemistry approach to determine structure activity relationships (SARs). The resulting molecules were assessed in vitro for their 5HT(1A) affinity and half-life in a heterologously expressed human CYP3A4 assay. Molecular features responsible for 5-HT(1A) affinity and CYP3A4 stability are described.
authors.affiliation: ArQule Inc, 19 Presidential Way, Woburn, MA 01801, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Tandon
authors.forename: Mary-Margaret
authors.initials: MM
authors.lastname: O'Donnell
authors.forename: Alex
authors.initials: A
authors.lastname: Porte
authors.forename: David
authors.initials: D
authors.lastname: Vensel
authors.forename: Donglai
authors.initials: D
authors.lastname: Yang
authors.forename: Rocio
authors.initials: R
authors.lastname: Palma
authors.forename: Alan
authors.initials: A
authors.lastname: Beresford
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ashwell
mesh_terms: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D018490:Serotonin Agents / Q000138:chemical synthesis / Q000378:metabolism*
chemical_list: D008024:Ligands; D010879:Piperazines; D018490:Serotonin Agents; D044282:Receptor, Serotonin, 5-HT1A; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human