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The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline (17e, MK-1421).

Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-a-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress. KEYWORDS: sstr3, antagonist, Type-2 diabetes, β-tetrahydrocarboline, carboxylic acid, hERG channel, QTc prolongation, cardiovascular dog models S omatostatin receptor 3 (sstr3) is a member of a group of five G-protein coupled somatostatin receptors (sstr1− sstr5). 1 Two different structural classes of selective small molecule sstr3 antagonists have been reported: imidazolyltetrahydro-β-carbolines derived from D-tryptophan (D-Trp) and substituted decahydroisoquinolines. 2−6 Recently, we disclosed that antagonism of sstr3 represents a potential novel mechanism for the treatment of Type-2 diabetes mellitus (T2DM) through the evaluations of compound 1 in both in vitro assays and animal efficacy models (Figure 1). 7 Subsequently, we reported that the optimization of this tetrahydro-β-carboline series led to the discovery of MK-4256 (Figure 1). 8 MK-4256 possesses excellent sstr3 potency and subtype selectivity, a good pharmacokinetic (PK) profile in preclinical species, and superior efficacy in a mouse oGTT assay. Although, MK-4256 was shown to have high protein plasma binding with ∼1% free fractions across several species (Table 1), only a minimal shift (∼2×) was observed from in vitro assays with 20% human serum added (Figure 1). 9 This lack of serum shift on sstr3 was attributed to a slow dissociation rate of MK-4256 from the receptor. More significantly, MK-4256 reduced glucose excursion by 86% in a mouse oGTT assay at a dose as low as 0.1 mg/kg with the maximal plasma concentration of 88 nM. 8 On the other hand, MK-4256 had

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Brain changes associated with risperidone, a dopamine-2/serotonin-2 receptor antagonist, have been documented in rats and humans, but not in nonhuman primates. This study characterized brain changes associated with risperidone in nonhuman primates. Rhesus monkeys were orally administered risperidone in a dose-escalation paradigm up to a maximum tolerated dose of 0.5 mg/kg/day for 3 weeks, or 3 months followed by a 3-month recovery period. Transient and fully reversible neurological signs consistent with risperidone pharmacology were observed. The results of a magnetic resonance imaging evaluation after 3 months of treatment and at the end of the 3-month recovery period showed no meaningful changes in the brain. There were no risperidone-related brain weight changes or gross findings. Histomorphological evaluation of brain sections stained with hematoxylin and eosin, ionized calcium binding adaptor molecule 1 (Iba1), and luxol fast blue/cresyl violet double staining showed no notable differences between control and risperidone groups. However, evaluation of the brain after glial fibrillary acidic protein (GFAP) immunohistochemical staining revealed increased staining in the cell bodies and processes of astrocytes in the putamen without apparent alterations in numbers or distribution. The increase in GFAP staining was present after 3 weeks and 3 months of treatment, but no increase in staining was observed after the 3-month recovery period, demonstrating the reversibility of this finding. The reversible increase in GFAP expression was likely an adaptive, non-adverse response of astrocytes, associated with the pharmacology of risperidone. These observations are valuable considerations in the nonclinical risk assessment of new drug candidates for psychiatric disorders.