TITLE: Pharmacokinetic-Pharmacodynamic Modeling of Biomarker Response and Tumor Growth Inhibition to an Orally Available cMet Kinase Inhibitor in Human Tumor Xenograft Mouse Models DMD #19711 2 RUNNING TITLE: PKPD Modeling of cMet Inhibitor in Tumor Xenog

CL/F, oral clearance; EC 50 , drug concentration causing 50% of maximum effect; CV, coefficients of variation; E 0 , baseline of cMet phosphorylation; EC 90 , drug concentration causing 90% of maximum effect; E max , maximum effect; f u , free fraction in plasma; γ, Hill coefficient; HGF, hepatocyte growth factor; HPLC, high performance liquid chromatography; k a , absorption rate constant; k e0 , the rate constant for equilibration with the effect site; k in , formation rate constant; k out , degradation rate constant; LC- The model fitted the time-courses of cMet phosphorylation well, suggesting that the main reason for the hysteresis is a rate-limiting distribution from plasma into tumor. The EC 50 and EC 90 values were estimated to be 19 ng/mL and 167 ng/mL, respectively. For tumor growth inhibition, the exponential tumor growth model fitted the time-course of individual tumor growth inhibition well. The EC 50 for the GTL16 tumor growth inhibition was estimated to be 213 ng/mL. Thus, the EC 90 for the inhibition of cMet phosphorylation corresponded to the EC 50 for the tumor growth inhibition, suggesting that near-complete inhibition of cMet phosphorylation (>90%) is required to significantly inhibit tumor growth (>50%). The present results will be helpful in DMD #19711 5 determining the appropriate dosing regimen and in guiding dose escalation to rapidly achieve efficacious systemic exposure in the clinic

Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: Identification of candidates for clinical development

The pre-clinical characterization of novel aryloxypyridine amides that are histamine H3 receptor antagonists is described. These compounds are high affinity histamine H3 ligands that penetrate the CNS and occupy the histamine H3 receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates

A Dipolar Cycloaddition Reaction To Access 6‑Methyl-4,5,6,7-tetrahydro‑1<i>H</i>‑[1,2,3]­triazolo[4,5‑<i>c</i>]­pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure–activity relationships of the new compounds are described. Two of these compounds, (<i>S</i>)-(2-fluoro-3-(trifluoromethyl)­phenyl)­(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridin-5-yl)­methanone (compound <b>29</b>) and (<i>S</i>)-(3-fluoro-2-(trifluoromethyl)­pyridin-4-yl)­(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridin-5-yl)­methanone (compound <b>35</b>), were found to have robust P2X7 receptor occupancy at low doses in rat with ED₅₀ values of 0.06 and 0.07 mg/kg, respectively. Compound <b>35</b> had notable solubility compared to <b>29</b> and showed good tolerability in preclinical species. Compound <b>35</b> was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders

Novel Octahydropyrrolo[3,4‑<i>c</i>]pyrroles Are Selective Orexin‑2 Antagonists: SAR Leading to a Clinical Candidate

The preclinical characterization of novel octahydro­pyrrolo­[3,4-<i>c</i>]­pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochemical and DMPK properties led to the discovery of compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment of primary insomnia. The synthesis, SAR, and optimization of the pharmacokinetic properties of this series of compounds as well as the identification of the clinical candidate, JNJ-42847922 (<b>34</b>), are described herein

Identification of (<i>R</i>)‑(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro‑1<i>H</i>‑imidazo[4,5‑<i>c</i>]pyridin-5(4<i>H</i>)‑yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor

The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo­[4,5-<i>c</i>]­pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo­[4,5-<i>c</i>]­pyridines ultimately leading to the identification of <b>1</b> (JNJ 54166060). <b>1</b> is a potent P2X7 antagonist with an ED₅₀ = 2.3 mg/kg in rats, high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD. Additionally, <b>1</b> possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism

Lead Optimization of 5‑Aryl Benzimidazolone- and Oxindole-Based AMPA Receptor Modulators Selective for TARP γ‑8

Glutamate mediates fast excitatory neurotransmission via ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, we describe the discovery, lead optimization, and preclinical characterization of 5-arylbenzimidazolone and oxindole-based negative modulators of AMPARs associated with TARP γ-8, the primary TARP found in hippocampus. High-throughput screen lead <b>4</b> was optimized for potency and brain penetration to provide benzimidazolone <b>3</b>, JNJ-55511118. Replacement of the benzimidazolone core in <b>3</b> with an oxindole mitigated reactive metabolite formation and led to the identification of <b>18</b> (GluA1/γ-8 pIC₅₀ = 9.7). Following oral dosing in rats, <b>18</b> demonstrated robust target engagement in hippocampus as assessed by <i>ex vivo</i> autoradiography (ED₅₀ = 0.6 mg/kg, plasma EC₅₀ = 9 ng/mL)

4‑Methyl-6,7-dihydro‑4<i>H</i>‑triazolo[4,5‑<i>c</i>]­pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate

The synthesis and preclinical characterization of novel 4-(<i>R</i>)-methyl-6,7-dihydro-4<i>H</i>-triazolo­[4,5-<i>c</i>]­pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4<i>H</i>-triazolo­[4,5-<i>c</i>]­pyridines, methyl substituted 5,6,7,8-tetrahydro­[1,2,4]­triazolo­[4,3-<i>a</i>]­pyrazines, and several other series lead to the identification of a series of 4-(<i>R</i>)-methyl-6,7-dihydro-4<i>H</i>-triazolo­[4,5-<i>c</i>]­pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (<b>14</b>) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein