Discovery of potent and selective orally bioavailable beta-substituted phenylalanine derived dipeptidyl peptidase IV inhibitors.
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.
Edmondson
Scott D
SD
Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065, USA. scott_edmondson@merck.com
Mastracchio
Anthony
A
Duffy
Joseph L
JL
Eiermann
George J
GJ
He
Huaibing
H
Ita
Ida
I
Leiting
Barbara
B
Leone
Joseph F
JF
Lyons
Kathryn A
KA
Makarewicz
Amanda M
AM
Patel
Reshma A
RA
Petrov
Aleksandr
A
Wu
Joseph K
JK
Thornberry
Nancy A
NA
Weber
Ann E
AE
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
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