Chem 250 - Advances in Pharmaceutical Research: From Lead Discovery to Drug Manufacturing - Spring 2011 - Caltech

Chemistry 250

Advances in Pharmaceutical Research:

From Lead Discovery to Drug Manufacturing - Spring 2011

References:

Week 2: Johnson & Johnson Services, Inc.

- Michael H. Rabinowitz -

1. Rabinowitz, Michael H.; Barrett, Terrance D.; Rosen, Mark D.; Venkatesan, Hariharan. Inhibitors of HIF prolyl hydroxylases. Annual Reports in Medicinal Chemistry (2010), 45 123-139.

2. Rosen, Mark D.; Venkatesan, Hariharan; Peltier, Hillary M.; Bembenek, Scott D.; Kanelakis, Kimon C.; Zhao, Lucy X.; Leonard, Barry E.; Hocutt, Frances M.; Wu, Xiaodong; Palomino, Heather L.; Brondstetter, Theresa I.; Haugh, Peter V.; Cagnon, Laurence; Yan, Wen; Liotta, Lisa A.; Young, Andrew; Mirzadegan, Tara; Shankley, Nigel P.; Barrett, Terrance D.; Rabinowitz, Michael H.. Benzimidazole-2-pyrazole HIF Prolyl 4-Hydroxylase Inhibitors as Oral Erythropoietin Secretagogues. ACS Medicinal Chemistry Letters (2010), 1(9), 526-529.

3. Kanelakis, Kimon C.; Palomino, Heather L.; Li, Lina; Wu, Jiejun; Yan, Wen; Rosen, Mark D.; Rizzolio, Michele C.; Trivedi, Meghana; Morton, Magda F.; Yang, Young; Venkatesan, Hariharan; Rabinowitz, Michael H.; Shankley, Nigel P.; Barrett, Terrance D. Characterization of a robust enzymatic assay for inhibitors of 2-oxoglutarate-dependent hydroxylases. Journal of Biomolecular Screening (2009), 14(6), 627-635.

- Jennifer Venable -

Week 3: Boehringer Ingelheim Pharmaceuticals, Inc.

- Keith R. Fandrick -

Asymmetric propargylation precedence:

J. Am. Chem. Soc. 1982, 104, 7667
J. Am. Chem. Soc. 1990, 112, 878
Org. Lett. 2006, 8, 4089
Tetrahedron 2003, 59, 9873 (Review)

Examples of use of amino alcohol ligands for asymmetric propargylation in total synthesis:

J. Am. Chem. Soc. 2002, 124, 1664
J. Org. Chem. 2002, 68, 4008

Additional background papers:

J. Org. Chem. 2005, 5235
J. Am. Chem. Soc. 2007, 15872
Adv. Synth. Catal. 2008, 2329
J. Org. Chem. 1986, 432
J. Am. Chem. Soc. 2005, 11572

The methodology:

J. Am. Chem. Soc. 2010, 132, 7600

Week 4: Merck & Co., Inc.

- John A. McCauley -
Nature 426, 186-189
J. Am. Chem. Soc. 2008, 130, 4607-4609
J. Med. Chem. 2010, 53, 2443
Antimicrob. Agents Chemother. 2011, 55, 937-939

- Cheng Y. Chen -
Tet. Lett. 1994, 38, 6981
J. Org. Chem. 1997, 62, 2676
Ang. Chem. Int. Ed. 2008, 47, 4231
J. Med. Chem. 2006, 49, 7584
J. Am. Chem. Soc. 1994, 3231 (sparteine mediated asymmetric deprotonation)
J. Org. Chem. 1997, 7726 (pyrrolidine-aryl coupling)
J. Am. Chem. Soc. 2006, 3538

Week 5: Abbott Laboratories

- Michael R. Michaelides -

Kinase background:
Science 2002, 298, 1912
Curr. Top. Med. Chem. 2007, 1408-1422

Thienopyrimidine ureas as KDR inhibitors:
Bioorg. Med. Chem. Lett. 2000, 10, 2167
Bioorg. Med. Chem. Lett. 2002, 12, 1683
Bioorg. Med. Chem. Lett. 2002, 12, 1687

Design criteria for oral bioavailability:
J. Med. Chem. 2010, 4830

Improving solubility:
J. Med. Chem. 2011, 1539
J. Med. Chem. 2007, 5858

Tumor growth inhibition versus time over target:
Mol. Cancer Ther. 2006, 995

- Michael J. Rozema -

Org. Process Res. Dev. 2009, 13 (6), pp 1419-1425

Week 6: Amgen, Inc.

- Andrew S. Tasker -

Crystal structure of the tyrosine kinase domain of the human insulin receptor:
Nature 1994, 746-754
EMBO J. 1997, 5572-81

- Wenge Zhong -

Strategies to optimize brain penetration in drug discovery:
Curr. Opin. Drug Discov. Rev. 2005, 8, 505-12

Property-guided application to CNS drugs:
J. Med. Chem. 2006, 49, 7559-7583

2-Aminoquinoline as a new Asp binder:
J. Med. Chem. 2007, 50, 1116-1123

Week 7: Cytokinetics, Inc.

- Bradley Morgan -

Plasma protein binding:
Clin. Pharm. Therapeutics 2002, 71 (3), 115-121

Chicken structure:
Science 1993, 261, 50

Scallop structure:
PNAS 2000, 97 (21), 11238-11243
Structure 2003, 11 (12), 1621-1627
Nature 2003, 424, 341-345

Omecamtiv discovery:
ACS Med. Chem. Lett. 2010, 1 (9), 472-477

Cardiac myosin activation:
Science 2011, 331, 1439-1443

- Jeremy Green -

Structure pf K11017 bound to Falcipain:
JBC 2009, 284, 25697

X-ray structure of HCV NS3.4A protease:
Cell 1996, 87, 343-355

Natural substrate:
Biochem. 1997, 36,9340

P1-P4 aldehyde inhibitor:
BMCL 2003, 13,4059

Replacement of aldehyde functionality:
BMCL 2004, 14, 1441

Proline-based P2 affords similar enzyme activity:
BMCL 2004, 14, 1939

P2 synthesis:
JOC 1994, 59, 2773

- Gerald J. Tanoury -

(R)-Proline from pyrrolidine:
JACS 1991, 113, 9708
JACS 1994, 116, 3231
JOC 1995, 60, 7092

(S)-Proline from pyrrolidine:
JACS 2002, 124, 11870

Mechanism & kinetics for bicycloproline:
JOC 1995, 60, 7092
JACS 2004, 126,15480

"Achiral" sparteine:
J. Het. Chem. 1976, 13, 1111
Synthesis 2001, 364

Week 9: Genentech

- Janet Gunzner and Timothy Heffron -

Lewis Phillips GD et al. Cancer Res (2008)
Junttila et al. Breast Can Res & Treatment (2010)
Perez EA et al. Abstr LBA3.ESMO 2010
www.biooncology.com

- David Askin -

Asymmetric hydrogenation:
Tetrahedron Lett. 1995, 36, 6419-6422

Highly diastereoselective iodohydrin formation:
Tetrahedron 1996, 52, 3327-3338

Synthesis of sultams:
Org. Lett. 2003, 5, 4175-4177

Pd-catalyzed N-arylation of sultams:
Tetrahedron Lett. 2004, 3305-3307

Claisen-type [3,3] rearrangement speculated:
J. Hetero. Chem. 1979, 1423

Corrected B3LYP energies and relevant transition structures (w/ K. N. Houk):
ACIE 2008, 47/22, 4134-4136