Lorlatinib is a novel, highly potent, brain‐penetrant, third‐generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad‐spectrum potency against most known resistance mutations that can develop during treatment with crizotinib and second‐generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100 mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid‐lowering agent. Prescription of supportive therapy should also consider the potential for drug‐drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100 mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK‐positive metastatic non‐small cell lung cancer previously treated with a second‐generation ALK TKI. Implications for Practice Despite the advancement of second‐generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK‐positive non‐small cell lung cancer. Lorlatinib is a potent, brain‐penetrant, third‐generation, macrocyclic ALK/ROS1 TKI, with broad‐spectrum potency against most known resistance mutations that can develop during treatment with existing first‐ and second‐generation ALK TKIs. This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.

We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain.

ABSTRACT:We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays. KEYWORDS:Fatty acid amide hydrolase, FAAH, oxazole, pyrazole, neuropathic pain, inflammatory pain, MK-4409, enzyme, inhibitor, CNS F atty acid amide hydrolase (FAAH) is an integral, membrane-bound enzyme responsible for the breakdown of fatty acid ethanolamide (FAE) signaling molecules, such as the endocanabinoid arachidonyl ethanolamide (anandamide, AEA), N-palmitoyl ethanolamide (PEA), and N-oleoyl ethanolamide (OEA). FAAH is a member of the serine hydrolase amidase signature family, which utilizes an unusual serine−serine−lysine catalytic triad. 1,2 Inhibition of FAAH leads to elevated levels of these endogenous FAEs, which act on cannabinoid receptors implicated in the suppression of pain transmission. 3 Levels of these FAEs were shown to be significantly elevated in FAAH knockout (KO) mice as compared to wild-type controls. 4 Both genetic knockout of FAAH and pharmacological modulation of FAAH activity demonstrated reduced sensitivity to pain. 5 Thus, FAAH inhibitors are expected to provide therapeutic benefits in the management of inflammatory and neuropathic pain. 6−9 Several classes of covalent and noncovalent FAAH inhibitors have been reported to date (Figure 1). Several covalent FAAH inhibitors that irreversibly inhibit FAAH by carbamylation of Ser241 have been reported and are exemplified by [10][11][12] A second subclass of FAAH inhibitors are the keto-oxazole class of FAAH inhibitors as exemplified by OL-135, 13 which reversibly forms an enzymestabilized hemiketal through a particularly reactive electrophilic carbonyl. More recently, however, several scaffolds have been disclosed as reversible noncovalent modifying inhibitors of

We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring.

10504 Background: Lorlatinib, a potent ALK inhibitor, exerts unprecedented activity against neuroblastoma (NB) derived xenografts harboring common crizotinib-resistant ALK mutations, leading to a first in child phase I study. Methods: R/R NB patients (pts) > 12 months, with ALK mutations/amplification and prior ALK inhibitor (ALKi) treatment were eligible. Lorlatinib was administered in 28-day courses (C). For pts < 18 years, 5 dose levels (DL) (45, 60, 75, 95, 115 mg/m2/day) were assessed. DL5 (115 mg/m2/day) expansion is enrolling (cohort A1). For patients > 18 years, two DL (DL3a the adult RP2D of 100 mg/day and DL4a at 150mg/day) were assessed (cohort A2). Primary endpoint was dose-limiting toxicity (DLT) during C1 and neurocognitive toxicity through C2. Blood samples for circulating tumor DNA (ctDNA) were matched to radiologic restaging. Results: From 9/2017 to 1/2019, 33 eligible patients enrolled (13 with prior ALKi therapy), with median age (range) 5.5 years (2-17) on A1, 21.5 years (15-50) on A2. In A1, 3 pts each enrolled onto DL1-3, with no DLT’s. 5/10 pts enrolled on DL4, with no DLT’s. 1/3 on DL5 had a DLT of grade 3 diarrhea, with expansion ongoing. In cohort A2, 5 patients enrolled at 100 mg/day with no DLT’s; 6 enrolled at 150 mg/day, with one DLT (grade 4 reversible psychosis). Most common treatment-related adverse events were weight gain (90%, grade 1-3), hyperlipidemia (90%, grade 1-3), concentration/memory impairment (23%, grade 1-2), peripheral neuropathy (13%; grade 1-2, A2 only), and peripheral edema (10%; grade 1, A2 only). Lorlatinib steady state exposure at DL3 and DL4 was in the range of exposures seen in adult lung cancer patients at the 100 mg and 200 mg DLs. In A1, 1/18 had partial response (PR), 3/18 had minor responses (MR), and 4/18 had stable disease (SD). Of pts with MR, 2/3 had PR of soft tissue and 1/3 had complete response (CR) by MIBG. In A2 pts, 1/10 had CR, 3/10 PR, and 3/10 MR; Notably, 2/3 with PR had CR by MIBG. Of the pts with MR, one had PR and one CR by MIBG. Responses occurred across dose levels, ALK mutations, and in ALKi pre-treated pts with median courses of 2 (1-24) on A1 and 10.5 (2-28) on A2. Serial ctDNA results showed mutant ALK variant allele frequency trajectories that correlated with clinical response and emergence of novel ALK mutations in cis that corresponded with disease progression. Conclusions: Inhibition of ALK-driven NB with lorlatinib occurs with manageable toxicity and objective anti-tumor activity. Prospective ctDNA allows for monitoring of disease and evolution of resistance. Clinical trial information: NCT03107988.

The objective of this study was to understand outcomes of patients treated with ALK inhibitors, especially when ALK inhibitors are followed by other ALK inhibitors. A systematic literature review was conducted in PubMed, Embase, and Cochrane through July 17, 2017. Conference abstracts (three meetings in past 2 years) also were searched. Of 504 unique publications, 80 met inclusion criteria (47 clinical trials, 33 observational studies). Observational studies have the potential to provide information for ALK inhibitors used sequentially. Ten observational studies reported median overall survival of crizotinib-led sequences ranging from 30.3 to 63.75 months from initiation of crizotinib; 49.4-89.6 months from metastatic non-smallcell lung cancer diagnosis; and 15.5-22.0 months from initiation of the second-generation ALK inhibitor after initial crizotinib. Sequencing of ALK inhibitors may benefit patients progressing on initial ALK inhibitors.

Introduction: Around 3–5% of non-small cell lung cancers (NSCLC) are ALK-positive. Crizotinib was the first approved ALK inhibitor from clinical trials. However, there are less data on the utilization and patient outcomes associated with crizotinib in real-world clinical practice. Methods: This was a retrospective, observational study of adult crizotinib-treated ALK-positive metastatic NSCLC patients who received treatment between 1 September 2011 and 31 October 2014, with follow up through 31 December 2015. Data were obtained via programmatic queries of the US Oncology Network/McKesson Specialty Health electronic health record database, supplemented with chart abstraction. Overall survival (OS) and time to treatment failure (TTF) were estimated from crizotinib initiation using the Kaplan–Meier (KM) method. Results: Of the n = 199 ALK-positive crizotinib-treated patients meeting eligibility criteria, crizotinib was prescribed as first line (1 L) in n = 123 (61.8%). The majority (88.9%) had confirmed adenocarcinoma histology and 32.2% had brain metastases at initial diagnosis. Median age at crizotinib initiation was 60.2 years (range 27.1–88.2); 54.8% were never smokers, 33.7% were former smokers. Treatment of 250 mg, twice daily, was most commonly prescribed (89.5%) with the dose unchanged from an initial dose in 79.4% of patients. The primary discontinuation reason was progression (n = 91, 58.7%). Patients (3.2%) were identified as discontinuing crizotinib as a result of treatment-related toxicity. With median follow-up time of 13.0 months (min–max = 0.03–46.6), median OS from crizotinib initiation was 33.8 months (95% CI = 24.3–38.8). Median TTF was 10.4 months. Conclusions: Crizotinib usage evaluated within the real-world setting is consistent with prior phase III clinical trial data, and illustrates the real-world effectiveness of crizotinib.

We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.KEYWORDS MK-5046, bombesin receptor subtype-3 agonist, obesity T he mammalian bombesin G-protein-coupled receptor subfamily 1 comprises three structurally related members, the receptors for neuromedin B (NMBR or BB1), gastrin-releasing peptide (GRPR or BB2), 2 and bombesin receptor subtype-3 (BRS-3 or BB3). 3 BRS-3 is an orphan receptor whose natural ligand is not known and which, despite its name, does not bind bombesin with high affinity. BRS-3 is expressed predominantly in the central nervous system (CNS). Mice lacking functional BRS-3 develop mild obesity and insulin resistance, suggesting a role for the receptor in the regulation of energy homeostasis. 4 In addition, BRS-3 as well as the other mammalian family members are expressed by several human carcinoma cell lines, where they may play a role in growth regulation. 3 Until recently, there have been limited reports of peptide 5 or smallmolecule 6-9 pharmacological tools to further elucidate the role of the receptor and determine its potential as a drug target.Our laboratory has described the lead identification and initial optimization of the first reported series of smallmolecule BRS-3 agonists with efficacy in body weight lowering. [10][11][12] Exploratory medicinal chemistry efforts focused on lead 1. The potency at the human receptor was improved through the incorporation of branched substituents at the 4-position of the imidazole, while systemic and CNS exposure were increased through replacement of the benzoic acid moiety with pyridine. This work eventually led to the identification of 2 (Bag-1), the first key pharmacological tool in our program. Results of in vivo testing with this compound furnished a preclinical proof of concept for the BRS-3 mechanism: Administration of the BRS-3 agonist in established diet-induced obese (eDIO) mice caused a significant reduction of acute food intake and increase in fasting metabolic rate, and these effects were not evident in Brs3 null (KO) mice. 13 Furthermore, subchronic dosing (100 mpk BID, 8 days) led to mechanism-based body weight lowering in eDIO mice, while it had no significant effects in KO mice. 13 Undesirable features of 2 were its poor oral pharmacokinetics in preclinical species and a suboptimal off-target profile that included low micromolar binding to the human inward rectifying potassium ion channel (hERG, IC 50 = 1.2 μM) as well as the diltiazem (DLZ) site of the rabbit calcium ion channel (IC 50 = 0.5 μM).The low unbound exposure of compound 2 was shown to be due primarily to high intrinsic clearance. A bile duct cannulated rat study was performed to examine the fate of the compound after in vivo dosing. For this purpose, a tritium radiolabel was incorporated in the 5-position of th...