title: Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists.
abstract: We report SAR studies on a novel non-peptidic somatostatin receptor 3 (SSTR3) agonist lead series derived from (4-phenyl-1H-imidazol-2-yl)methanamine. This effort led to the discovery of a highly potent low molecular weight SSTR3 agonist 5c (EC50=5.2 nM, MW=359). The results from molecular overlays of 5c onto the L-129 structure indicate good alignment, and two main differences of the proposed overlays of the antagonist MK-4256 onto the conformation of 5c lead to inversion of antagonism to agonism.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA. Electronic address: zhong_lai@merck.com.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Lai
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Shuwen
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Sherer
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Ball
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: David X
authors.initials: DX
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Liangqing
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Derun
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Quang
authors.initials: Q
authors.lastname: Tuang
authors.affiliation: Department of Diabetes Research, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.affiliation: Department of Diabetes Research, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Dorina
authors.initials: D
authors.lastname: Trusca
authors.affiliation: Department of Diabetes Research, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Kwei-Lan
authors.initials: KL
authors.lastname: Tsao
authors.affiliation: Department of Diabetes Research, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Zhou
authors.affiliation: Department of Diabetes Research, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D055808:Drug Discovery; D006801:Humans; D008744:Methylamines / Q000737:chemistry*; D017481:Receptors, Somatostatin / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D008744:Methylamines; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; C027451:methylamine
keywords: (4-Phenyl-1H-imidazol-2-yl)methanamine; Somatostatin receptor 3 (SSTR3) agonist; Structural overlay