Substituted fused bicyclic pyrrolizinones as potent, orally bioavailable hNK1 antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 6, 2010, Pages 2007-2012

  Morriello, Gregori J ^a   Mills, Sander G ^a   Johnson, Tricia ^a   Reibarkh, Mikhail ^a   Chicchi, Gary ^a   DeMartino, Julie ^a   Kurtz, Marc ^a   Davies, P ^a   Tsao, K L C ^a   Zheng, Song ^a   Tong, Xinchun ^a   Carlson, Emma ^a   Townson, Karen ^a   Tattersall, F D ^a   Wheeldon, Alan ^a   Boyce, Susan ^a   Collinson, Neil ^a   Rupniak, Nadia ^a   Moore, Stephen ^a   DeVita, Robert J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Neurokinin 1 antagonist; Nuerokinin receptor; Substance P

Indexed keywords

BICYCLIC PYRROLIZINONE DERIVATIVE; BICYCLO COMPOUND; NEUROKININ 1 RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BRAIN; CONTROLLED STUDY; DOG; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG PENETRATION; DRUG POTENCY; DRUG SYNTHESIS; GERBIL; HUMAN; HUMAN CELL; IN VIVO STUDY; NONHUMAN; RHESUS MONKEY; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ADMINISTRATION, ORAL; ANIMALS; BICYCLO COMPOUNDS; BIOLOGICAL AVAILABILITY; HUMANS; PYRROLES; RECEPTORS, NEUROKININ-1;

GERBILLINAE;

EID: 77449100425     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.01.065     Document Type: Article

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27. Unpublished metabolite profiling from rat PK data indicate that ketone 4 is formed in vitro and in vivo from analog 2b.
28. In effort to conserve space in the table, the other diastereomer,which would be 15b, was not included. The intrinsic binding for 15b was 0.11 nM and 1.8 nM in the presence of 50% human serum, with ion channel affinity of 558 nM for sodium and 1358 nM for the calcium channels. Functional IP-1 was 63% SP remaining and GFT inhibition was mesured at 100% inh at 3 mpk iv at 24 h.
29. The relative stereochemistry of 2b was determined by use of 2D NOE NMR of both diasteromers (2a and 2b). The most crucial evidence that determined the sterochemistry of 2b was the presence of an NOE signal between the alpha hydrogen adjancent to the hydroxyl substituent and the bridgehead hydrogen of the fuse pyrrolidine ring. This would indicate that the hydroxyl group is in the (S)-configuration. This NOE signal was also absent in its diastereomer, 2a.
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