Discovery of potent and selective β-homophenylalanine based dipeptidyl peptidase IV inhibitors

Xu, Jinyou; Ok, Hyun; Gonzalez, Edward J.; Colwell, Lawrence F.; Habulihaz, Bahanu; He, Huaibing; Leiting, Barbara; Lyons, Kathryn A.; Marsilio, Frank; Patel, Reshma A.; Wu, Joseph K.; Thornberry, Nancy A.; Weber, Ann E.; Parmee, Emma R.

doi:10.1016/j.bmcl.2004.06.099

Cited by 58 publications

(17 citation statements)

References 17 publications

(5 reference statements)

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“…These lead compounds were ultimately optimized to give vildagliptin 31, 90 and saxagliptin 91, 92 (Onglyza; Bristol Myers Squibb). Sitagliptin 93 (Januvia; Merck) and linagliptin 94 (Tradjenta; Boehringer Ingelheim), in contrast, were both optimized from novel structures—a β-amino acid scaffold 95 and xanthene-based scaffold 94 , respectively—identified from screening compound libraries. Finally, alogliptin emerged from medicinal chemistry efforts around a quinazolinone scaffold predicted to inhibit the active-site of DPP-4 by structure-based design 86 .…”

Section: Clinically Approved Inhibitors Of Human Serine Hydrolasesmentioning

confidence: 99%

The pharmacological landscape and therapeutic potential of serine hydrolases

Bachovchin

Cravatt

2012

Nat Rev Drug Discov

257

337

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Serine hydrolases play critical roles in many biological processes, and several are targets of approved drugs for indications such as type 2 diabetes, Alzheimer’s disease, and infectious disease. Despite this, most of the 200+ human serine hydrolases remain poorly characterized with respect to their physiological substrates and functions, and the vast majority lack selective, in vivo-active inhibitors. Here, we review the current state of pharmacology for mammalian serine hydrolases, including marketed drugs, compounds under clinical investigation, and selective inhibitors emerging from academic probe development efforts. We also highlight recent methodological advances that have accelerated the rate of inhibitor discovery and optimization for serine hydrolases, which we anticipate will aid in their biological characterization and, in some cases, therapeutic validation.

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Section: Clinically Approved Inhibitors Of Human Serine Hydrolasesmentioning

confidence: 99%

The pharmacological landscape and therapeutic potential of serine hydrolases

Bachovchin

Cravatt

2012

Nat Rev Drug Discov

257

337

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“…1 Derivatives of betahomophenylalanine and in particular those of compound 1 (Scheme 1) 2 have recently been reported to be potential new treatments for type II diabetes. 3 Methods have been developed in these laboratories to prepare compounds such as 1 in enantiomerically pure form by asymmetric reduction of the corresponding beta-keto ester 2 4 followed by a Mitsunobu reaction.…”

Section: Introductionmentioning

confidence: 99%

Application of the asymmetric hydrogenation of enamines to the preparation of a beta-amino acid pharmacophore

Kubryk

Hansen

2006

Tetrahedron: Asymmetry

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“…1). 1 In the course of our investigation of the SAR of a structurally distinct screening lead 2, we were interested to learn the impact of a similar substitution. Thus, we have found that a marked boost in DP-IV inhibitory potency could be achieved by the incorporation of a (R)-b-amino amide moiety into the left-hand side of the molecule to give compounds such as 3.…”

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confidence: 99%