ADMET / PK

Representative SERx compounds were submitted to the National Institutes of Health subcontractor CROs to delineate absorption, distribution, metabolism, and toxicity (ADMET) parameters. Evaluation at 50 CNS/peripheral sites indicate low (Ki > 1 mM) or nil (Ki > 5 mM) affinity for adenylyl cyclase, adenosine, adrenergic, benzodiazepine, cholinergic, dopamine, GABAA, hERG, histamine; opiate, NMDA, PCP, PLC, sigma, DAT, NET, SERT, ion channels (Ca++, Cl, K+). Functional studies indicate hERG activity is nil (IC50 > 2.0 µM), thus, no cardiotoxicity is expected; our own results document no activation of 5HT2B GPCRs (no cardiotoxicity). DAT functional activity also was nil. The inhibitory effects on CYP activity in human liver microsomes was measured for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4—no inhibition was observed at 10 µM. Also, no toxicity was observed to human hepatocyte Fa2N-4 cells. Incubation at 10 and 100 µM with rat, rabbit, dog, monkey, and human liver microsomes indicated predictable N,N-dealkylated and aromatic hydroxylated metabolites. Leads are currently scheduled to undergo GMP IND-enabling ADMET studies by Aptuit LLC (Verona, Italy).

In vivo pharmacokinetics: SERx chemotypes are orally active in rodent models of autism spectrum disorder, psychoses, schizophrenia, addiction (psychostimulants, ethanol, opioids) and other compulsive behavioral disorders such as binge-eating. For example, SERx – 519 is neurobehaviorally active after oral administration for at least 3-hours; 1-2 µg levels in mouse brain at 30, 60, and 90 min (plasma levels at 10% of brain levels for all time points)

Below is the data for SERx – 519 taken from lead paper. Canal CE, Felsing DE, Liu Y, Zhu W, Wood JT, Perry CK, Vemula R, Booth RG. An Orally-Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist that Corrects Motor Stereotypy in Mouse Models. ACS Chem Neurosci. 2015; 6:1259-1270. PMID:26011730.

ADMET 1

ADMET 2