title: Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist.
abstract: The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, AstraZeneca Pharmaceuticals, 35 Gatehouse Drive, Waltham, MA 02451, USA. minli.zhang@astrazeneca.com
authors.forename: Minli
authors.initials: M
authors.lastname: Zhang
authors.forename: Diansong
authors.initials: D
authors.lastname: Zhou
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Donna L
authors.initials: DL
authors.lastname: Maier
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Widzowski
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Sobotka-Briner
authors.forename: Becky J
authors.initials: BJ
authors.lastname: Brockel
authors.forename: William M
authors.initials: WM
authors.lastname: Potts
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Shenvi
authors.forename: Peter R
authors.initials: PR
authors.lastname: Bernstein
authors.forename: M Edward
authors.initials: ME
authors.lastname: Pierson
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000032:analysis; D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001578:Benzopyrans / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004311:Double-Blind Method; D006168:Guinea Pigs; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007036:Hypothermia, Induced; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects*; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology; D057170:Translational Research, Biomedical
chemical_list: C558331:(2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide; D018435:ATP Binding Cassette Transporter, Subfamily B; D014151:Anti-Anxiety Agents; D001578:Benzopyrans; D009025:Morpholines; D044302:Receptor, Serotonin, 5-HT1B; D058829:Serotonin 5-HT1 Receptor Antagonists; D017366:Serotonin Receptor Agonists