Edward R. Bacon

Identification of pyridazin-3-one derivatives as potent, selective histamine H3 receptor inverse agonists with robust wake activity

H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model.

Amine-constrained pyridazinone histamine H3 receptor antagonists

Pyridazinone 1 was recently reported as a potent H(3)R antagonist with good drug-like properties and in vivo activity. A series of constrained amine analogs of 1 was synthesized to identify compounds with improved pharmacokinetic profiles. From these efforts, a new class of (S)-2-pyrrolidin-1-ylmethyl-1-pyrrolidinyl amides was identified.

Design and synthesis of dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases.

Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure-activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity.

Discovery of 7-arylsulfonyl-1,2,3,4, 4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridines: Identification of a potent and selective 5-HT6 receptor antagonist showing activity in rat social recognition test

Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ∼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat social recognition test.

Wake-promoting agents: Search for next generation modafinil: Part I

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.

Novel morpholine ketone analogs as potent histamine H3 receptor inverse agonists with wake activity

Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.

Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists.

Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model.

Wake promoting agents: search for next generation modafinil, lessons learned: part III.

In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an active metabolite (compound 3).

From an Atypical Wake-promoting Agent to Potent Histamine-3 Receptor Inverse Agonists

Utilizing atypical wake‐promoting agent modafinil (inactive in both rH3 and hH3 binding assays) as a launching pad, a series of sulfinyl‐ and sulfone‐derived H3 receptor inverse agonists were developed. Brain‐permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H1, H2, and H4 receptors).

Aryl-Heteroaryl Derivatives as Novel Wake-Promoting Agents

In search of a next generation molecule to the novel wake‐promoting agent modafinil, a series of aryl‐heteroayl‐derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually.