Brett D. Allison

Discovery of a novel series of selective HCN1 blockers.

The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.

Indole- and benzothiophene-based histamine H3 antagonists.

Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.

Anthranilic sulfonamide CCK1/CCK2 dual receptor antagonists I: Discovery of CCKR1 selectivity in a previously CCKR2-selective lead series

A series of CCK2R-selective anthranilic amides is shown to derive CCK1R affinity via selective substitution of the amide side chain. Thus, extending the length of the original benzamide side chain by a single methylene unit imparts CCK1R affinity to the series, and further fine tuning of the affinity results in CCK1R selectivity of greater than 100-fold.

4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]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-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]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 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.

1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines as TRPV1 antagonists with improved properties.

Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure-activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 ≥237 μg/mL and SIF=11 μg/mL) was significantly improved over compound 1 (pH 2=5 μg/mL and SIF=0.5 μg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL=0.7 L/kg/h) compared to compound 1 (CL=3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats.

Discovery of potent cholecystokinin-2 receptor antagonists: elucidation of key pharmacophore elements by X-ray crystallographic and NMR conformational analysis.

A novel series of cholecystokinin-2 receptor (CCK-2R) antagonists has been identified, as exemplified by anthranilic sulfonamide 1 (pK(i)=7.6). Pharmacokinetic and stability studies indicated that this series of compounds suffered from metabolic degradation, and that both the benzothiadiazole and piperidine rings were rapidly oxidized by liver enzymes. A combination of synthesis, computational methods, (1)H NMR conformational studies, and X-ray crystallographic analyses were applied to elucidate key pharmacophore elements, and to discover analogs with improved pharmacokinetic profiles, and high receptor binding affinity and selectivity.

JNJ-26070109 [( R )4-Bromo- N -[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide]: A Novel, Potent, and Selective Cholecystokinin 2 Receptor Antagonist with Good Oral Bioavailability

JNJ-26070109 [(R)4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide] is a representative of a new chemical class of competitive antagonists of cholecystokinin 2 (CCK2) receptors. In this study, the primary in vitro pharmacology of JNJ-26070109 was evaluated along with the pharmacokinetic and pharmacodynamic properties of this compound in rat and canine models of gastric acid secretion. JNJ-26070109 expressed high affinity for human (pKI = 8.49 ± 0.13), rat (pKI = 7.99 ± 0.08), and dog (pKI = 7.70 ± 0.14) CCK2 receptors. The selectivity of JNJ-26070109 at the CCK2 receptor versus the CCK1 receptor was species-dependent, with the greatest degree of selectivity (>1200-fold) measured at the human isoforms of the CCK1 receptor (selectivity at CCK2 versus CCK1 receptors: human, ∼1222-fold; rat, ∼324-fold; dog ∼336-fold). JNJ-26070109 behaved as a surmountable, competitive, antagonist of human CCK2 receptors in a calcium mobilization assay (pKB = 8.53 ± 0.05) and in pentagastrin-stimulated gastric acid secretion in the isolated, lumen-perfused, mouse stomach assay (pKB = 8.19 ± 0.13). The pharmacokinetic profile of this compound was determined in vivo in rats and dogs. JNJ-26070109 was shown to have high oral bioavailability (%F rat = 73 ± 16; %F dog = 92 ± 12) with half lives of 1.8 ± 0.3 and 1.2 ± 0.1 h in rat and dog, respectively. The pharmacodynamic properties of this compound were investigated using two in vivo models. In conscious rat and dog chronic gastric fistula models of pentagastrin-stimulated acid secretion, JNJ-26070109 had oral EC50 values of 1.5 and 0.26 μM, respectively. Overall, we have demonstrated that JNJ-26070109 is a high-affinity, selective CCK2 receptor antagonist with good pharmacokinetic properties.