| 14723956 |
Lee J, Kang SU, Lim JO, Choi HK, Jin MK, Toth A, Pearce LV, Tran R, Wang Y, Szabo T, Blumberg PM: N-[4-(methylsulfonylamino) benzyl] thiourea analogues as vanilloid receptor antagonists: analysis of structure-activity relationships for the "C-Region". Bioorg Med Chem. 2004 Jan 15;12(2):371-85.
We recently reported that N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino) benzyl] thiourea (2) was a high affinity antagonist of the vanilloid receptor with a binding affinity of K (i)=63 nM and an antagonism of K (i)=53.9 nM in rat VR1 heterologously expressed in Chinese hamster ovary (CHO) cells (Mol. Pharmacol. 2002, 62, 947-956). In an effort to further improve binding affinity and antagonistic potency, we have modified the C-region of the lead 4-t-butylbenzyl group with diverse surrogates, such as araalkyl, alkyl, 4-alkynylbenzyl, indanyl, 3,3-diarylpropyl, 4-alkoxybenzyl, 4-substituted piperazine and piperidine. The lipophilic surrogates, arylalkyl and alkyl, conferred modest decreases in binding affinities and antagonistic potencies; the groups having heteroatoms resulted in dramatic decreases. Our findings indicate that 4-t-butylbenzyl is one of the most favorable groups for high receptor binding and potent antagonism to VR1 in this structural series. |
2(0,0,0,2) |