2. Academic Validation
  3. Discovery and Preclinical Profiling of GSK3839919, a Potent HIV-1 Allosteric Integrase Inhibitor

Discovery and Preclinical Profiling of GSK3839919, a Potent HIV-1 Allosteric Integrase Inhibitor

  • ACS Med Chem Lett. 2022 May 9;13(6):972-980. doi: 10.1021/acsmedchemlett.2c00115.
Kyle Parcella 1,  Tao Wang 2,  Kyle Eastman 2,  Zhongxing Zhang 2,  Zhiwei Yin 2,  Manoj Patel 1,  Yong Tu 2,  Barbara Zhizhen Zheng 2,  Michael A Walker 2,  Mark G Saulnier 2,  David Frennesson 2,  Michael Bowsher 1,  Eric Gillis 1,  Kevin Peese 1,  Makonen Belema 2,  Christopher Cianci 2,  Ira B Dicker 1,  Brian McAuliffe 1,  Bo Ding 1,  Paul Falk 1,  Jean Simmermacher 1,  Dawn D Parker 1,  Prasanna Sivaprakasam 2,  Kevin Kish 2,  Hal Lewis 2,  Umesh Hanumegowda 1,  Susan Jenkins 1,  John F Kadow 1,  Mark Krystal 1,  Nicholas A Meanwell 2,  B Narasimhulu Naidu 1
Affiliations

Affiliations

  • 1 ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States.
  • 2 Research and Early Development, Bristol Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
PMID: 35707159 DOI: 10.1021/acsmedchemlett.2c00115
Abstract

Allosteric HIV-1 integrase inhibitors (ALLINIs) have been of interest recently because of their novel mechanism of action. Strategic modifications to the C5 moiety of a class of 4-(4,4-dimethylpiperidinyl)-2,6-dimethylpyridinyl ALLINIs led to the identification of a tetrahydroisoquinoline heterocycle as a suitable spacer element to project the distal hydrophobic aryl ring. Subsequent optimization of the aryl substitutions identified 12 as an ALLINI with single-digit nanomolar inhibitory potency and low clearance across preclinical species. In preclinical toxicology studies with 12 in rats, lipid hepatocellular vacuolation was observed. Removal of the C6 methyl group resulted in GSK3839919 (22), which exhibited a reduced incidence and severity of lipid vacuolation in both in vitro assays and in vivo studies while maintaining the potency and pharmacokinetic (PK) properties of the prototype. The virology, PK, and toxicology profiles of 22 are discussed.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z