title: Discovery of potent and selective orally bioavailable beta-substituted phenylalanine derived dipeptidyl peptidase IV inhibitors.
abstract: anti-Substituted biaryl beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors that suffer from suboptimal selectivity and pharmacokinetics. This letter describes the substitution of the beta-methyl substituent with beta-polar substituents, culminating in the discovery of a beta-dimethylamide substituted phenylalanine derivative with an excellent potency, selectivity, and pharmacokinetic profile.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA. scott_edmondson@merck.com
authors.forename: Scott D
authors.initials: SD
authors.lastname: Edmondson
authors.forename: Anthony
authors.initials: A
authors.lastname: Mastracchio
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Duffy
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.forename: Huaibing
authors.initials: H
authors.lastname: He
authors.forename: Ida
authors.initials: I
authors.lastname: Ita
authors.forename: Barbara
authors.initials: B
authors.lastname: Leiting
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Leone
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Lyons
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Makarewicz
authors.forename: Reshma A
authors.initials: RA
authors.lastname: Patel
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Petrov
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wu
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010649:Phenylalanine / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism; D000071230:Transcriptional Regulator ERG
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D011480:Protease Inhibitors; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D010649:Phenylalanine; D018819:Dipeptidyl Peptidase 4