Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors.
Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test.
Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Dmitri A
DA
Pissarnitski
Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Zhiqiang
Z
Zhao
Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
David
D
Cole
Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Wen-Lian
WL
Wu
Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Martin
M
Domalski
Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
John W
JW
Clader
Department of Structural Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Giovanna
G
Scapin
Department of Structural Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Johannes
J
Voigt
In Vitro Pharmacology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Aileen
A
Soriano
In Vitro Pharmacology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Theresa
T
Kelly
In Vivo Pharmacology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Mary Ann
MA
Powles
In Vivo Pharmacology, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Zuliang
Z
Yao
Department of Medicinal Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd., Kenilworth, NJ 07033, United States.
Duane A
DA
Burnett
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005951:Glucose Tolerance Test; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D014970:Xanthines; D006147:Guanine; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
Bioisosteres; DPP4 inhibitor; FAP inhibitor; Tricyclic guanine