title: 2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors.
abstract: TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
authors: Department of Chemistry, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA. chaoyang.dai@merck.com
authors: Chaoyang
authors: C
authors: Dai
authors: Dansu
authors: D
authors: Li
authors: Janeta
authors: J
authors: Popovici-Muller
authors: Lianyun
authors: L
authors: Zhao
authors: Vinay M
authors: VM
authors: Girijavallabhan
authors: Kristin E
authors: KE
authors: Rosner
authors: Brian J
authors: BJ
authors: Lavey
authors: Razia
authors: R
authors: Rizvi
authors: Bandarpalle B
authors: BB
authors: Shankar
authors: Michael K C
authors: MK
authors: Wong
authors: Zhuyan
authors: Z
authors: Guo
authors: Peter
authors: P
authors: Orth
authors: Corey O
authors: CO
authors: Strickland
authors: Jing
authors: J
authors: Sun
authors: Xiaoda
authors: X
authors: Niu
authors: Shiying
authors: S
authors: Chen
authors: Joseph A
authors: JA
authors: Kozlowski
authors: Daniel J
authors: DJ
authors: Lundell
authors: John J
authors: JJ
authors: Piwinski
authors: Neng-Yang
authors: NY
authors: Shih
authors: M Arshad
authors: MA
authors: Siddiqui
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry*; D051381:Rats; D013644:Tartrates / Q000737:chemistry*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D013644:Tartrates; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat; C029768:tartaric acid