Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines

Hong Lin; Dennis S. Yamashita; Ren Xie; Jin Zeng; Wenyong Wang; Jack Leber; Igor G. Safonov; Sharad Verma; Mei Li; Louis LaFrance; Joseph Venslavsky; Dennis Takata; Juan I. Luengo; Jason A. Kahana; Shuyun Zhang; Kimberly A. Robell; Dana Levy; Rakesh Kumar; Anthony E. Choudhry; Michael Schaber; Zhihong Lai; Barry S. Brown; Brian T. Donovan; Elisabeth A. Minthorn; Kristin K. Brown; Dirk A. Heerding

doi:10.1016/j.bmcl.2009.11.061

Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines

Hong Lin, Dennis S. Yamashita, Ren Xie, Jin Zeng, Wenyong Wang, Jack Leber, Igor G. Safonov, Sharad Verma, Mei Li, Louis LaFrance, Joseph Venslavsky, Dennis Takata, Juan I. Luengo, Jason A. Kahana, Shuyun Zhang, Kimberly A. Robell, Dana Levy, Rakesh Kumar, Anthony E. Choudhry, Michael SchaberZhihong Lai, Barry S. Brown, Brian T. Donovan, Elisabeth A. Minthorn, Kristin K. Brown, Dirk A. Heerding

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3β and tumor growth in a BT474 tumor xenograft model in mice.

Original language	English (US)
Pages (from-to)	684-688
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2009.11.061
State	Published - Jan 15 2010
Externally published	Yes

Keywords

AKT kinase inhibitors
Aminopyridines

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2009.11.061

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Lin, H., Yamashita, D. S., Xie, R., Zeng, J., Wang, W., Leber, J., Safonov, I. G., Verma, S., Li, M., LaFrance, L., Venslavsky, J., Takata, D., Luengo, J. I., Kahana, J. A., Zhang, S., Robell, K. A., Levy, D., Kumar, R., Choudhry, A. E., ... Heerding, D. A. (2010). Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines. Bioorganic and Medicinal Chemistry Letters, 20(2), 684-688. https://doi.org/10.1016/j.bmcl.2009.11.061

Lin, H, Yamashita, DS, Xie, R, Zeng, J, Wang, W, Leber, J, Safonov, IG, Verma, S, Li, M, LaFrance, L, Venslavsky, J, Takata, D, Luengo, JI, Kahana, JA, Zhang, S, Robell, KA, Levy, D, Kumar, R, Choudhry, AE, Schaber, M, Lai, Z, Brown, BS, Donovan, BT, Minthorn, EA, Brown, KK & Heerding, DA 2010, 'Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 2, pp. 684-688. https://doi.org/10.1016/j.bmcl.2009.11.061

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title = "Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines",

abstract = "The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3β and tumor growth in a BT474 tumor xenograft model in mice.",

keywords = "AKT kinase inhibitors, Aminopyridines",

author = "Hong Lin and Yamashita, {Dennis S.} and Ren Xie and Jin Zeng and Wenyong Wang and Jack Leber and Safonov, {Igor G.} and Sharad Verma and Mei Li and Louis LaFrance and Joseph Venslavsky and Dennis Takata and Luengo, {Juan I.} and Kahana, {Jason A.} and Shuyun Zhang and Robell, {Kimberly A.} and Dana Levy and Rakesh Kumar and Choudhry, {Anthony E.} and Michael Schaber and Zhihong Lai and Brown, {Barry S.} and Donovan, {Brian T.} and Minthorn, {Elisabeth A.} and Brown, {Kristin K.} and Heerding, {Dirk A.}",

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doi = "10.1016/j.bmcl.2009.11.061",

language = "English (US)",

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pages = "684--688",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Tetrasubstituted pyridines as potent and selective AKT inhibitors

T2 - Reduced CYP450 and hERG inhibition of aminopyridines

AU - Lin, Hong

AU - Yamashita, Dennis S.

AU - Xie, Ren

AU - Zeng, Jin

AU - Wang, Wenyong

AU - Leber, Jack

AU - Safonov, Igor G.

AU - Verma, Sharad

AU - Li, Mei

AU - LaFrance, Louis

AU - Venslavsky, Joseph

AU - Takata, Dennis

AU - Luengo, Juan I.

AU - Kahana, Jason A.

AU - Zhang, Shuyun

AU - Robell, Kimberly A.

AU - Levy, Dana

AU - Kumar, Rakesh

AU - Choudhry, Anthony E.

AU - Schaber, Michael

AU - Lai, Zhihong

AU - Brown, Barry S.

AU - Donovan, Brian T.

AU - Minthorn, Elisabeth A.

AU - Brown, Kristin K.

AU - Heerding, Dirk A.

PY - 2010/1/15

Y1 - 2010/1/15

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AB - The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3β and tumor growth in a BT474 tumor xenograft model in mice.

KW - AKT kinase inhibitors

KW - Aminopyridines

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Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines

Abstract

Keywords

ASJC Scopus subject areas

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