title: Fused tricyclic pyrrolizinones that exhibit pseudo-irreversible blockade of the NK1 receptor.
abstract: Previously, we had disclosed a novel class of hNK(1) antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK(1) affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK(1) compounds and to improve functional activity, we have designed and synthesized a new class of hNK(1) antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK(1) antagonists maintain subnanomolar hNK(1) binding affinity with highly improved functional IP-1 activity (<10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (<2% SP remaining), hNK(1) binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24h in the gerbil foot-tapping model with an ID(50) of 0.02 mpk at both 0 and 24h, respectively.
authors: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. greg_morriello@merck.com
authors: Gregori J
authors: GJ
authors: Morriello
authors: Gary
authors: G
authors: Chicchi
authors: Tricia
authors: T
authors: Johnson
authors: Sander G
authors: SG
authors: Mills
authors: Julie
authors: J
authors: Demartino
authors: Marc
authors: M
authors: Kurtz
authors: K L C
authors: KL
authors: Tsao
authors: Song
authors: S
authors: Zheng
authors: Xinchun
authors: X
authors: Tong
authors: Emma
authors: E
authors: Carlson
authors: Karen
authors: K
authors: Townson
authors: Alan
authors: A
authors: Wheeldon
authors: Susan
authors: S
authors: Boyce
authors: Neil
authors: N
authors: Collinson
authors: Nadia
authors: N
authors: Rupniak
authors: Robert J
authors: RJ
authors: Devita
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D006801:Humans; D008253:Macaca mulatta; D008861:Microsomes / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D011759:Pyrrolidines / Q000737:chemistry*; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000929:Antidepressive Agents, Tricyclic; D064729:Neurokinin-1 Receptor Antagonists; D011759:Pyrrolidines; D018040:Receptors, Neurokinin-1; C032519:pyrrolidine