John E. Munroe
Eli Lilly and Company
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Featured researches published by John E. Munroe.
Investigational New Drugs | 2005
Jian Liang; Richard E. Moore; Eric D. Moher; John E. Munroe; Rima S. Al-awar; David A. Hay; David L. Varie; Tony Y. Zhang; James Abraham Aikins; Michael J. Martinelli; Chuan Shih; James E. Ray; Lowell Lee Gibson; Vasu Vasudevan; Lisa Polin; Kathryn White; Juiwanna Kushner; Chiab Simpson; Susan Pugh; Thomas H. Corbett
SummaryCryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d × 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr [a pgp (+) MDR tumor]: 0%T/C, 3.2 LK; Mam 16/C/Adr [a pgp (−) MDR tumor]: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 [a pgp (+) MDR tumor]: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.
Tetrahedron | 1989
Norris E. Allen; Donald B. Boyd; Jack B. Campbell; Jack B. Deeter; Thomas K. Elzey; Bennie Joe Foster; Lowell D. Hatfield; Joseph N. Hobbs; William Joseph Hornback; David C. Hunden; Noel D. Jones; Michael Dean Kinnick; John M. Morin; John E. Munroe; John K. Swartzendruber; David G. Vogt
Abstract Computational chemistry made possible the prediction of the three-dimensional structures of γ-lactam analogues of penems and carbapenems before the analogues were made. Molecular superpositioning showed that these novel structures with a 7β-acylamino side-chain present the pharmacophoric groups in close spatial similarity to the groups in biologically active cephalosporin and penicillin antibiotics. This suggests that 8-oxo-7-acylamino-1-azabicyclo[3.3.0]-oct-2-ene-2-carboxylates and the 4-thia-analogues can be accommodated in the same active sites of essential bacterial penicillin-binding proteins where cephalosporins and penicillins are recognized. The syntheses of these compounds are reported. The γ-lactams exhibit low, but detectable levels of antibacterial activity and suggest promise that substantial activity can be achieved with other γ-lactams.
Tetrahedron Letters | 1986
Donald B. Boyd; Bennie Joe Foster; Lowell D. Hatfield; William Joseph Hornback; Noel D. Jones; John E. Munroe; John K. Swartzendruber
Abstract γ-Lactam analogues of carbapenems have been synthesized using a [3+2] cyclization approach. Slight antibiotic activity was observed in one case.
Bioorganic & Medicinal Chemistry Letters | 1995
John E. Munroe; Timothy Alan Shepherd; Louis Nickolaus Jungheim; William Joseph Hornback; Steve D. Hatch; Mark A. Muesing; MaryAnn Wiskerchen; Kenneth S. Su; Kristina M. Campanale; Angela J. Baxter; Joseph M. Colacino
Abstract Novel noncoded D-amino acids have been combined with decahydroisoquinoline, octahydrothienopyridine, and urea hydroxyethylamine isosteres to provide potent HIV-1 protease inhibitors with excellent HIV-1 antiviral activity. LY314613 shows a promising combination of potency and oral bioavailability. Trends in the SAR and comparisons to other isostere derivatives will be discussed.
Bioorganic & Medicinal Chemistry Letters | 1995
John E. Munroe; William Joseph Hornback; Jack B. Campbell; Michael A. Ouellette; Steve D. Hatch; Mark A. Muesing; Mary Ann Wiskerchen; Angela J. Baxter; Ken Su; Kristina M. Campanale
Abstract Replacement of the decahydroisoquinoline group contained in Ro 31-8959 by a cis -octahydrothienopyridine moiety has provided a high affinity hydroxyethylamine isostere for use in HIV-1 protease inhibitors. Further gains in potency have been realized by incorporation of a sulfur atom into the P 1 benzyl group. Modification by a key P 2 ligand provided LY316440, a potent, orally absorbed inhibitor of HIV-1 protease.
Bioorganic & Medicinal Chemistry Letters | 1998
Gwendolyn Kay Cook; William Joseph Hornback; John H. McDonald; John E. Munroe; Nancy June Snyder
The enhanced stability of the carbacephem nucleus over the corresponding cephalosporin nucleus has allowed the synthesis of 7-arylglycyl-3-trifluoromethyl-carbacephems. These unique carbacephems possess broad spectrum activity and high stability to both plasmid and chromosomally mediated beta-lactamases.
Journal of The Chemical Society-perkin Transactions 1 | 2001
Scott C. Mauldin; William Joseph Hornback; John E. Munroe
The synthesis of (2Z,4RS)-5-acetamido-4-guanidino-2-benzamidopent-2-enoic acid (sodium salt) 5 is reported. Wittig–Horner olefination of diamino protected propionaldehyde 8 with phosphonoglycine trimethyl ester 11 provided (Z)-olefin methyl ester 12. The methyl ester was converted to allyl ester 15 by initial hydrolysis with lithium hydroxide followed by reaction with allyl bromide. Target compound 5 was prepared from allyl ester 15 by initial formation of bis(Boc)guanidino ester 16 followed by treatment with tetrakis(triphenylphosphine)palladium(0). The product was evaluated for activity against influenza neuraminidase and was found to be weakly active.
Bioorganic & Medicinal Chemistry Letters | 1995
William Joseph Hornback; John E. Munroe; Timothy Alan Shepherd; Steve D. Hatch; Mark A. Muesing; MaryAnn Wiskerchen; Joseph M. Colacino; Angela J. Baxter; Kenneth S. Su; Kristina M. Campanale
Abstract Using the hydroxyethylamine isosteres 1 and 2 containing the novel cis-octahydrothienopyridine moiety, substantial enhancement of binding potencies for HIV-1 protease inhibitors which incorporate carbamate linked heterocyclic P2 ligands has been realized. This increase in binding has led to a very potent antiviral compound (LY326188). The pharmacokinetics of selected derivatives are detailed in this report.
Journal of Medicinal Chemistry | 1995
Charles Pidgeon; Shaowei. Ong; Hanlan Liu; Xiaoxing Qiu; Mary Pidgeon; Anne H. Dantzig; John E. Munroe; William Joseph Hornback; Jeffery S. Kasher
AIDS | 1996
Bruce A. Dressman; James Erwin Fritz; Marlys Hammond; William Joseph Hornback; Stephen W. Kaldor; Vincent J. Kalish; John E. Munroe; Siegfried Heinz Reich; John Howard Tatlock; Timothy Alan Shepherd; Michael J. Rodriguez