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 H3 receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity |
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| Institution: | 1. Autoridad Regulatoria Nuclear, Av. Del Libertador 8250, 1429 Buenos Aires, Argentina;2. Instituto de Tecnología, UADE, Lima 717, (C1073AAO) Buenos Aires and Autoridad Regulatoria Nuclear, Av. Del Libertador 8250, 1429 Buenos Aires, Argentina;1. Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India;2. Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India;3. DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India;4. Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, UK;5. Biosciences, Infection iMed, AstraZeneca, Waltham, MA, USA;1. Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA;2. Discovery Biology, Cardiovascular, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA;3. Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA;1. School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, Brisbane 4072, Australia;2. School of Pharmacy, University of Queensland, St. Lucia, Brisbane 4072, Australia |
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| Abstract: | A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo4.1.0]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-bicyclo4.1.0]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. |
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| Keywords: | CEP-26401 Pyridazin-3-one Sleep–wake Cognition |
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