Optimization of a novel D 2 dopamine receptor antagonist with unprecedented selectivity as a therapeutic to treat psychosis and other neuropsychiatric disorders

The D 2 dopamine receptor (D2R) is one of the most validated drug targets in psychiatry and there is a strong correlation between the clinical doses of antipsychotics and their potencies for blocking D2Rs. However, current FDA‐approved antipsychotic drugs typically cross‐react with other GPCRs, leading to many deleterious side‐effects. Using high throughput screening, we have identified and characterized a lead D2R antagonist with high selectivity – ML321. ML321 shows little GPCR cross‐reactivity beyond inhibition of the D2R, and to a lesser extent the D3R, demonstrating exceptional GPCR selectivity. Behavioral assays in rodents demonstrate ML321’s efficacy in models that are predictive of antipsychotic effects in humans (e.g., attenuation of both amphetamine and PCP‐induced locomotor activity and pre‐pulse inhibition). Importantly, using doses that are maximally effective in antipsychotic‐predictive assays, ML321 promotes little to no catalepsy, suggesting that ML321 may produce fewer extrapyramidal side effects in patients (an on‐target side effect). This property may be due to unique binding kinetics of ML321 at the D2R. Importantly, no other D2R antagonist exhibits this pharmacological and behavioral profile, which supports ML321’s promise as a superior therapeutic. No concerns were noted during safety/toxicity studies including hERG channel activation, cytotoxicity, an AMES test, and a CYP inhibition study. ML321 demonstrates good brain penetrability (20% vs. plasma), but also exhibits a relatively short half‐life in vivo of about 2 hr. The latter represents an impediment to the advancement of this antipsychotic candidate into clinical studies. A metabolite study was performed using human hepatocytes, which revealed that the primary ML321 metabolites involve oxidation of the alkyl‐thiophene portion of the molecule. Thus, in an attempt to create more metabolically stable derivatives of ML321, we have systematically altered the scaffold via modification or replacement of the thiophene moiety which is likely to lead to significantly greater stability. Preliminary SAR studies (Xiao et. al., J. Med. Chem ., 57:3450, 2014)) have demonstrated that replacement of the thiophene can be accomplished without significant alteration of the scaffold’s pharmacological properties. Approximately 50 such ML321 analogs have been synthesized and are being characterized pharmacologically using D2R radioligand binding and functional (b‐arrestin recruitment) assays. In parallel, these structural analogs are being assessed in vitro for ADME in order to determine their metabolic stability, solubility and predicted penetrability. Overall, our expectation is that the ML321 scaffold can be optimized into an advanced drug candidate with the potential for targeting schizophrenia and other psychotic syndromes involving the D2R.