Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: A bench-to-bedside case study on tissue selective drug distribution

✍ Scribed by Jeffrey A. Pfefferkorn; John Litchfield; Richard Hutchings; Xue-Min Cheng; Scott D. Larsen; Bruce Auerbach; Mark R. Bush; Chitase Lee; Noe Erasga; Daniel M. Bowles; David C. Boyles; Gina Lu; Catherine Sekerke; Valerie Askew; Jeffrey C. Hanselman; Lisa Dillon; Zhiwu Lin; Andrew Robertson; Karl Olsen; Carine Boustany; Karen Atkinson; Theunis C. Goosen; Vaishali Sahasrabudhe; Jonathan Chupka; David B. Duignan; Bo Feng; Renato Scialis; Emi Kimoto; Yi-An Bi; Yurong Lai; Ayman El-Kattan; Rebecca Bakker-Arkema; Paul Barclay; Erick Kindt; Vu Le; Jaap W. Mandema; Mark Milad; Bradley D. Tait; Robert Kennedy; Bharat K. Trivedi; Mark Kowala

• Publisher: Elsevier Science
• Year: 2011
• Tongue: English
• Weight: 435 KB
• Volume: 21
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.11.103

✦ Synopsis

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.