title: Optimization of 5-pyridazin-3-one phenoxypropylamines as potent, selective histamine H₃ receptor antagonists with potent cognition enhancing activity.
abstract: Previous studies have shown that (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH(3)R K(i) = 2.8 nM) and rat H(3)Rs (rH(3)R K(i) = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R(2) and R(6) positions to improve the pharmacokinetic properties over 2 led to the identification of 5-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin-2-yl-2H-pyridazin-3-one 29. Compound 29 displayed high affinity for both human and rat H(3)Rs (hH(3)R K(i) = 1.7 nM, rH(3)R K(i) = 3.7 nM) with a greater than 1000-fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H(3)R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity.
authors: Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States. mtao@cephalon.com
authors: Ming
authors: M
authors: Tao
authors: Lisa D
authors: LD
authors: Aimone
authors: Zeqi
authors: Z
authors: Huang
authors: Joanne
authors: J
authors: Mathiasen
authors: Rita
authors: R
authors: Raddatz
authors: Jacquelyn
authors: J
authors: Lyons
authors: Robert L
authors: RL
authors: Hudkins
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D054314:Drug Inverse Agonism; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009152:Mutagenicity Tests; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011437:Propylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013894:Thirst / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: C570917:5-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2-pyridin-2-yl-2H-pyridazin-3-one; D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D018697:Nootropic Agents; D011437:Propylamines; D011724:Pyridazines; D018100:Receptors, Histamine H3