Synthesis and SAR of 4-aminocyclopentapyrrolidines as orally active N-type calcium channel inhibitors for inflammatory and neuropathic pain

…, D Darczak, S Shekhar, TA Vortherms, L Miller…

Index: Beebe, Xenia; Yeung, Clinton M.; Darczak, Daria; Shekhar, Shashank; Vortherms, Timothy A.; Miller, Loan; Milicic, Ivan; Swensen, Andrew M.; Zhu, Chang Z.; Banfor, Patricia; Wetter, Jill M.; Marsh, Kennan C.; Jarvis, Michael F.; Scott, Victoria E.; Schrimpf, Michael R.; Lee, Chih-Hung Bioorganic and Medicinal Chemistry Letters, 2013 , vol. 23, # 17 p. 4857 - 4861

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Citation Number: 7

Abstract

We recently reported 7 a potent and selective N-type calcium channel blocker 1 (Fig. 1) with efficacy in animal pain models when delivered intraperitoneal (ip). Herein we describe the discovery of orally efficacious N-type calcium channel blockers using a set of in vitro high throughput-ADME (HT-ADME) data in conjunction with Ca v 2.2 potency. The HT-ADME data allowed for optimization of pharmacokinetic properties to provide compounds for oral dosing in efficacy studies. ...