James V. Heck
Merck & Co.
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by James V. Heck.
Journal of Biological Chemistry | 2000
Sajjad A. Qureshi; Victor D.-H. Ding; Zhihua Li; Deborah Szalkowski; Dawn E. Biazzo-Ashnault; Dan Xie; Richard Saperstein; Edward J. Brady; Su Huskey; Xiaolan Shen; Kun Liu; Libo Xu; Gino Salituro; James V. Heck; David E. Moller; A. Brian Jones; Bei B. Zhang
We recently described the identification of a non-peptidyl fungal metabolite (l-783,281, compound 1), which induced activation of human insulin receptor (IR) tyrosine kinase and mediated insulin-like effects in cells, as well as decreased blood glucose levels in murine models of Type 2 diabetes (Zhang, B., Salituro, G., Szalkowski, D., Li, Z., Zhang, Y., Royo, I., Vilella, D., Diez, M. T., Pelaez, F., Ruby, C., Kendall, R. L., Mao, X., Griffin, P., Calaycay, J., Zierath, J. R., Heck, J. V., Smith, R. G. & Moller, D. E. (1999) Science 284, 974–977). Here we report the characterization of an active analog (compound 2) with enhanced IR kinase activation potency and selectivity over related receptors (insulin-like growth factor I receptor, epidermal growth factor receptor, and platelet-derived growth factor receptor). The IR activators stimulated tyrosine kinase activity of partially purified native IR and recombinant IR tyrosine kinase domain. Administration of the IR activators to mice was associated with increased IR tyrosine kinase activity in liver.In vivo oral treatment with compound 2 resulted in significant glucose lowering in several rodent models of diabetes. In db/db mice, oral administration of compound 2 elicited significant correction of hyperglycemia. In a streptozotocin-induced diabetic mouse model, compound 2 potentiated the glucose-lowering effect of insulin. In normal rats, compound 2 improved oral glucose tolerance with significant reduction in insulin release following glucose challenge. A structurally related inactive analog (compound 3) was not effective on insulin receptor activation or glucose lowering in db/db mice. Thus, small molecule IR activators exert insulin mimetic and sensitizing effects in cells and in animal models of diabetes. These results have implications for the future development of new therapies for diabetes mellitus.
Bioorganic & Medicinal Chemistry Letters | 2003
Ranjit C. Desai; Wei Han; Edward Metzger; Jeffrey P. Bergman; Dominick F. Gratale; Karen L. MacNaul; Joel P. Berger; Thomas W. Doebber; Kwan Leung; David E. Moller; James V. Heck; Soumya P. Sahoo
A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARα/γ agonists was identified. A number of highly potent and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.
Tetrahedron Letters | 1984
Alex Andrus; Beverly Partridge; James V. Heck; Burton G. Christensen
Abstract A series of N-(tetrazol-5-yl)azetidin-2-ones have been prepared from serine and threonine and evaluated as antibiotics against a range of bacteria.
Tetrahedron Letters | 1989
Michael J. Szymonifka; James V. Heck
Abstract The preparation of 4-carbomethoxy-1,2-thiazetidine-1,1-dioxides from carbomethoxymethanesulfonyl chloride and imines is described.
Tetrahedron Letters | 1981
James V. Heck; Burton G. Christensen
Abstract A synthesis of a cyclic analog of the β-lactam antibiotic nocardicin A and a new synthon for N-unsubstituted azetidinones is described.
Bioorganic & Medicinal Chemistry Letters | 2003
Ranjit C. Desai; Dominick F. Gratale; Wei Han; Hiroo Koyama; Edward Metzger; Victoria K. Lombardo; Karen L. MacNaul; Thomas W. Doebber; Joel P. Berger; Kwan Leung; Ronald B. Franklin; David E. Moller; James V. Heck; Soumya P. Sahoo
Abstract A series of novel aryloxazolidine-2,4-diones was synthesized. A structure–activity relationship study of these compounds led to the identification of potent, orally active PPAR dual α/γ agonists. Based on the results of efficacy studies in the db/db mice model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling.
Bioorganic & Medicinal Chemistry Letters | 2003
Hiroo Koyama; Julia K. Boueres; Wei Han; Edward Metzger; Jeffrey P. Bergman; Dominick F. Gratale; Daniel J. Miller; Richard L. Tolman; Karen L. MacNaul; Joel P. Berger; Thomas W. Doebber; Kwan Leung; David E. Moller; James V. Heck; Soumya P. Sahoo
A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.
Bioorganic & Medicinal Chemistry Letters | 1999
Robert R. Wilkening; Ronald W. Ratcliffe; Kenneth J. Wildonger; Lovji D. Cama; Kevin D. Dykstra; Frank P. DiNinno; Timothy A. Blizzard; Milton L. Hammond; James V. Heck; Karen Dorso; E.St. Rose; Joyce Kohler; Gail G. Hammond
A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.
Tetrahedron Letters | 1988
M.D. Lewis; J.P. Duffy; James V. Heck; R. Menes
Summary Triyne carbonate L-660,631 methyl ester ( 2 ) was synthesized in eight steps from cyclooctene. Synthetic methodology to permit systematic variation of the triyne portion of the molecule has been developed.
Bioorganic & Medicinal Chemistry Letters | 1999
Ronald W. Ratcliffe; Robert R. Wilkening; Kenneth J. Wildonger; Sherman T. Waddell; Gina M. Santorelli; D.L. Parker; Jerry D. Morgan; Timothy A. Blizzard; Milton L. Hammond; James V. Heck; Joann Huber; Joyce Kohler; Karen Dorso; E.St. Rose; Jon G. Sundelof; Walter J. May; Gail G. Hammond
A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.