title: Discovery of two clinical histamine H(3) receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764).
abstract: The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.
authors.affiliation: Pfizer Worldwide Research and Development, Groton, CT 06340-5159, USA. travis.t.wager@pfizer.com
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.forename: Betty A
authors.initials: BA
authors.lastname: Pettersen
authors.forename: Anne W
authors.initials: AW
authors.lastname: Schmidt
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Spracklin
authors.forename: Scot
authors.initials: S
authors.lastname: Mente
authors.forename: Todd W
authors.initials: TW
authors.lastname: Butler
authors.forename: Harry
authors.initials: H
authors.lastname: Howard
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lettiere
authors.forename: David M
authors.initials: DM
authors.lastname: Rubitski
authors.forename: Diane F
authors.initials: DF
authors.lastname: Wong
authors.forename: Frank M
authors.initials: FM
authors.lastname: Nedza
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Nelson
authors.forename: Hans
authors.initials: H
authors.lastname: Rollema
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Raggon
authors.forename: Jiri
authors.initials: J
authors.lastname: Aubrecht
authors.forename: Jody K
authors.initials: JK
authors.lastname: Freeman
authors.forename: John M
authors.initials: JM
authors.lastname: Marcek
authors.forename: Julie
authors.initials: J
authors.lastname: Cianfrogna
authors.forename: Karen W
authors.initials: KW
authors.lastname: Cook
authors.forename: Larry C
authors.initials: LC
authors.lastname: James
authors.forename: Linda A
authors.initials: LA
authors.lastname: Chatman
authors.forename: Philip A
authors.initials: PA
authors.lastname: Iredale
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Banker
authors.forename: Michael L
authors.initials: ML
authors.lastname: Homiski
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Munzner
authors.forename: Rama Y
authors.initials: RY
authors.lastname: Chandrasekaran
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D004285:Dogs; D004327:Drinking Behavior / Q000187:drug effects; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008064:Lipidoses / Q000139:chemically induced / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C569673:3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-N-(2-methylpropyl)cyclobutanecarboxamide; D001798:Blood Proteins; D003503:Cyclobutanes; D006633:Histamine Antagonists; C569672:N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidinylmethyl)phenyl)cyclobutanecarboxamide; D010743:Phospholipids; D011759:Pyrrolidines; D018100:Receptors, Histamine H3