3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake-promoting activity.

A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6. Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1R,6S)-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H3R candidate. Diastereomer 25 had high H3R binding affinity, excellent selectivity, displayed potent H3R functional antagonism and robust wake-promoting activity in vivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development.

Discovery of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a): histamine H(3) receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity.

A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.

Synthesis and evaluation of 4- and 5-pyridazin-3-one phenoxypropylamine analogues as histamine-3 receptor antagonists.

A novel series of 4-pyridazin-3-one and 5-pyridazin-3-one analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship revealed the 5-pyridazin-3-ones 8a and S-methyl 8b had excellent human and rat H(3)R affinities, and acceptable pharmacokinetic properties. In vivo evaluation of 8a showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG/EMG model.

Synthesis and evaluation of 4-alkoxy-[1'-cyclobutyl-spiro(3,4-dihydrobenzopyran-2,4'-piperidine)] analogues as histamine-3 receptor antagonists.

A novel class of 4-alkoxy-[1'-cyclobutyl-spiro(3,4-dihydrobenzopyran-2,4'-piperidine)] analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship identified sulfone 27 with excellent H(3)R affinities in both humans and rats, and acceptable pharmacokinetic properties. Further, compound 28 achieved single digit nanomolar H(3)R affinities in both species with minimum hERG activity.

Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent.

A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.

High specific activity tritiation of the pyridazin-3-one histamine H3 receptor inverse agonist CEP-27088.

Methods are presented to tritiate and characterize radioligand (3).

Synthesis and evaluation of pyridone-phenoxypropyl-R-2-methylpyrrolidine analogues as histamine H3 receptor antagonists.

6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]-phenyl}-2H-pyridazin-3-one 6 (Irdabisant; CEP-26401) was recently reported as a potent H(3)R antagonist with excellent drug-like properties and in vivo activity that advanced into clinical evaluation. A series of pyridone analogs of 6 was synthesized and evaluated as H(3)R antagonists. Structure-activity relationships revealed that the 5-pyridone regiomer was optimal for H(3)R affinity. N-Methyl 9b showed excellent H(3)R affinity, acceptable pharmacokinetics and pharmaceutical properties. In vivo evaluation of 9b showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG model.

Discovery and characterization of 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (CEP-26401, irdabisant): a potent, selective histamine H3 receptor inverse agonist.

Optimization of a novel series of pyridazin-3-one histamine H(3) receptor (H(3)R) antagonists/inverse agonists identified 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (8a, CEP-26401; irdabisant) as a lead candidate for potential use in the treatment of attentional and cognitive disorders. 8a had high affinity for both human (K(i) = 2.0 nM) and rat (K(i) = 7.2 nM) H(3)Rs with greater than 1000-fold selectivity over the hH(1)R, hH(2)R, and hH(4)R histamine receptor subtypes and against an in vitro panel of 418 G-protein-coupled receptors, ion channels, transporters, and enzymes. 8a demonstrated ideal pharmaceutical properties for a CNS drug in regard to water solubility, permeability and lipophilicity and had low binding to human plasma proteins. It weakly inhibited recombinant cytochrome P450 isoforms and human ether-a-go-go-related gene. 8a metabolism was minimal in rat, mouse, dog, and human liver microsomes, and it had good interspecies pharmacokinetic properties. 8a dose-dependently inhibited H(3)R agonist-induced dipsogenia in the rat (ED(50) = 0.06 mg/kg po). On the basis of its pharmacological, pharmaceutical, and safety profiles, 8a was selected for preclinical development. The clinical portions of the single and multiple ascending dose studies assessing safety and pharmacokinetics have been completed allowing for the initiation of a phase IIa for proof of concept.

Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors.

A novel series of C-3 urea, amide, and carbamate fused dihydroindazolocarbazole (DHI) analogs are reported as highly potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases with excellent cellular potency. Structure-activity relationship (SAR) studies indicate the optimal N-13 alkyl substitutions are n-propyl and i-butyl. The isopropyl carbamate 39 displayed good dual enzyme, cell potency, and rat pharmacokinetic properties for advancement to in vivo evaluation.

Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells.

The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of anaplastic large-cell lymphoma (ALCL) have been well defined; nevertheless, the notion that ALK is a molecular target for the therapeutic modulation of ALK+ ALCL has not been validated thus far. Select fused pyrrolocarbazole (FP)-derived small molecules with ALK inhibitory activity were used as pharmacologic tools to evaluate whether functional ALK is essential for the proliferation and survival of ALK+ ALCL cells in culture. These compounds inhibited interleukin 3 (IL-3)-independent proliferation of BaF3/NPM-ALK cells in an ALK inhibition-dependent manner and significantly blocked colony formation in agar of mouse embryonic fibroblast (MEF) cells harboring NPM-ALK. Inhibition of NPM-ALK phosphorylation in the ALK+ ALCL-derived cell lines resulted in significant inhibition of cell proliferation and induction of apoptotic-cell death, while having marginal effects on the proliferation and survival of K562, an ALK- leukemia cell line. ALK inhibition resulted in cell-cycle G1 arrest and inactivation of ERK1/2, STAT3, and AKT signaling pathways. Potent and selective ALK inhibitors may have therapeutic application for ALK+ ALCL and possibly other solid and hematologic tumors in which ALK activation is implicated in their pathogenesis.