NMS-03592088

F17464 (N-(3-{4-[4-(8-Oxo-8H-[1,3]-dioxolo-[4,5-g]-chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide, hydrochloride) is a new potential antipsychotic with a unique profile. The compound exhibits high affinity for the human dopamine receptor subtype 3 (hD₃) (K_i = 0.17 nM) and the serotonin receptor subtype 1a (5-HT_1a) (K_i = 0.16 nM) and a >50 fold lower affinity for the human dopamine receptor subtype 2 short and long form (hD_2s/l) (K_i = 8.9 and 12.1 nM, respectively). [¹⁴C]F17464 dynamic studies show a slower dissociation rate from hD₃ receptor (t1/2 = 110 min) than from hD_2s receptor (t1/2 = 1.4 min) and functional studies demonstrate that F17464 is a D₃ receptor antagonist, 5-HT_1a receptor partial agonist. In human dopaminergic neurons F17464 blocks ketamine induced morphological changes, an effect D₃ receptor mediated. In vivo F17464 target engagement of both D₂ and 5-HT_1a receptors is demonstrated in displacement studies in the mouse brain. F17464 increases dopamine release in the rat prefrontal cortex and mouse lateral forebrain - dorsal striatum and seems to reduce the effect of MK801 on % c-fos mRNA medium expressing neurons in cortical and subcortical regions. F17464 also rescues valproate induced impairment in a rat social interaction model of autism. All the neurochemistry and behavioural effects of F17464 are observed in the dose range 0.32-2.5 mg/kg i.p. in both rats and mice. The in vitro - in vivo pharmacology profile of F17464 in preclinical models is discussed in support of a therapeutic use of the compound in schizophrenia and autism.

More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy.