Zhenrong Xu
Boehringer Ingelheim
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Featured researches published by Zhenrong Xu.
ACS Medicinal Chemistry Letters | 2011
Lanqi Jia; Robert D. Simpson; Jing Yuan; Zhenrong Xu; Wei Zhao; Salvacion Cacatian; Colin M. Tice; Joan Guo; Alexey V. Ishchenko; Suresh B. Singh; Zhongren Wu; Brian M. McKeever; Yuri Bukhtiyarov; Judith A. Johnson; Christopher P. Doe; Richard K. Harrison; Gerard M. McGeehan; Lawrence W. Dillard; John J. Baldwin; David A. Claremon
Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.
Journal of Medicinal Chemistry | 2011
Zhenrong Xu; Colin M. Tice; Wei Zhao; Salvacion Cacatian; Yuanjie Ye; Suresh B. Singh; Peter Lindblom; Brian M. McKeever; Paula Krosky; Barbara A. Kruk; Jennifer Berbaum; Richard K. Harrison; Judith A. Johnson; Yuri Bukhtiyarov; Reshma Panemangalore; Boyd B. Scott; Yi Zhao; Joseph G. Bruno; Jennifer Togias; Joan Guo; Rong Guo; Patrick J. Carroll; Gerard M. McGeehan; Linghang Zhuang; Wei He; David A. Claremon
Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11β-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000× selectivity over 11β-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge.
Bioorganic & Medicinal Chemistry Letters | 2010
Colin M. Tice; Wei Zhao; Zhenrong Xu; Salvacion Cacatian; Robert D. Simpson; Yuanjie Ye; Suresh B. Singh; Brian M. McKeever; Peter Lindblom; Joan Guo; Paula Krosky; Barbara A. Kruk; Jennifer Berbaum; Richard K. Harrison; Judith J. Johnson; Yuri Bukhtiyarov; Reshma Panemangalore; Boyd B. Scott; Yi Zhao; Joseph G. Bruno; Linghang Zhuang; Gerard M. McGeehan; Wei He; David A. Claremon
Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.
Bioorganic & Medicinal Chemistry Letters | 2009
Colin M. Tice; Zhenrong Xu; Jing Yuan; Robert D. Simpson; Salvacion Cacatian; Patrick T. Flaherty; Wei Zhao; Joan Guo; Alexey V. Ishchenko; Suresh B. Singh; Zhongren Wu; Boyd B. Scott; Yuri Bukhtiyarov; Jennifer Berbaum; Jennifer M. Mason; Reshma Panemangalore; Maria Grazia Cappiello; Dominik Müller; Richard K. Harrison; Gerard M. McGeehan; Lawrence W. Dillard; John J. Baldwin; David A. Claremon
Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
Bioorganic & Medicinal Chemistry Letters | 2010
Zhenrong Xu; Salvacion Cacatian; Jing Yuan; Robert D. Simpson; Lanqi Jia; Wei Zhao; Colin M. Tice; Patrick T. Flaherty; Joan Guo; Alexey V. Ishchenko; Suresh B. Singh; Zhongren Wu; Brian M. McKeever; Boyd B. Scott; Yuri Bukhtiyarov; Jennifer Berbaum; Jennifer M. Mason; Reshma Panemangalore; Maria Grazia Cappiello; Ross Bentley; Christopher P. Doe; Richard K. Harrison; Gerard M. McGeehan; Lawrence W. Dillard; John J. Baldwin; David A. Claremon
Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.
Tetrahedron Letters | 2002
Xiaolin Li; Zhenrong Xu; Erin F. DiMauro; Marisa C. Kozlowski
Abstract Upon treatment with (PhIO) n or PhI(OAc) 2 , 1,5-diaza- cis -decalin undergoes oxidation at the more hindered position along with fragmentation to yield the ring-expanded bislactam. The cis and trans 1,5-diazadecalins both undergo the same elimination indicating a potential stereoelectronic preference for oxidation at the more substituted carbon alpha to the nitrogen. Oxidation at the less hindered positions of 1,5-diaza- cis -decalin was accomplished on the Boc-protected derivative to provide an intermediate for the synthesis of 2,6-substituted-1,5-diaza- cis -decalins.
Tetrahedron | 2001
Marisa C. Kozlowski; Zhenrong Xu; A. Gil Santos
Abstract The stereoselective synthesis of 2,6-dimethyl-1,5-diaza-cis-decalins with the dimethyl groups syn or anti to the angular hydrogens has been accomplished starting from 1,5-diaza-cis-decalin. From an NMR study of the conformational properties of all three 2,6-dimethyl-1,5-diaza-cis-decalins, the components which affect the conformational equilibrium have been identified.
Bioorganic & Medicinal Chemistry Letters | 2011
Jing Yuan; Robert D. Simpson; Wei Zhao; Colin M. Tice; Zhenrong Xu; Salvacion Cacatian; Lanqi Jia; Patrick T. Flaherty; Joan Guo; Alexey V. Ishchenko; Zhongren Wu; Brian M. McKeever; Boyd B. Scott; Yuri Bukhtiyarov; Jennifer Berbaum; Reshma Panemangalore; Ross Bentley; Christopher P. Doe; Richard K. Harrison; Gerard M. McGeehan; Suresh B. Singh; Lawrence W. Dillard; John J. Baldwin; David A. Claremon
Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.
Bioorganic & Medicinal Chemistry | 2017
Linghang Zhuang; Colin M. Tice; Zhenrong Xu; Wei Zhao; Salvacion Cacatian; Yuanjie Ye; Suresh B. Singh; Peter Lindblom; Brian M. McKeever; Paula Krosky; Yi Zhao; Deepak S. Lala; Barbara A. Kruk; Shi Meng; Lamont Howard; Judith A. Johnson; Yuri Bukhtiyarov; Reshma Panemangalore; Joan Guo; Rong Guo; Frank Himmelsbach; Bradford S. Hamilton; Annette Schuler-Metz; Heike Schauerte; Richard Gregg; Gerard M. McGeehan; Katerina Leftheris; David A. Claremon
A potent, in vivo efficacious 11β hydroxysteroid dehydrogenase type 1 (11β HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11β HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.
Archive | 2009
David A. Claremon; Linghang Zhuang; Katerina Leftheris; Colin M. Tice; Zhenrong Xu; Yuanjie Ye; Suresh B. Singh; Salvacion Cacatian; Wei Zhao