4-aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV.

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Duffy JL, Kirk BA, Wang L, Eiermann GJ, He H, Leiting B, Lyons KA, Patel RA, Patel SB, Petrov A, Scapin G, Wu JK, Thornberry NA, Weber AE

4-aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV.

Bioorg Med Chem Lett. 2007 May 15;17(10):2879-85. Epub 2007 Feb 25.

PubMed ID

17350841 [ View in PubMed

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Abstract

A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
6-(4-{(1S,2S)-2-AMINO-1-[(DIMETHYLAMINO)CARBONYL]-3-[(3S)-3-FLUOROPYRROLIDIN-1-YL]-3-OXOPROPYL}PHENYL)-1H-[1,2,4]TRIAZOLO[1,5-A]PYRIDIN-4-IUM	Dipeptidyl peptidase 4	IC 50 (nM)	4	7.5	37	Details
N-(TRANS-4-{(1S,2S)-2-AMINO-3-[(3S)-3-FLUOROPYRROLIDIN-1-YL]-1-METHYL-3-OXOPROPYL}CYCLOHEXYL)-N-METHYLACETAMIDE	Dipeptidyl peptidase 4	IC 50 (nM)	16	7.5	37	Details