346423-32-3Relevant academic research and scientific papers
The insulin secretory action of novel polycyclic guanidines: Discovery through open innovation phenotypic screening, and exploration of structure-activity relationships
Shaghafi, Michael B.,Barrett, David G.,Willard, Francis S.,Overman, Larry E.
, p. 1031 - 1036 (2014/03/21)
We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3- arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner.
Synthesis of polycyclic guanidines by cyclocondensation reactions of N-amidinyliminium ions
Overman,Wolfe
, p. 3167 - 3175 (2007/10/03)
A new method for the synthesis of polycyclic guanidines is described. The N-amidinyliminium ion generated from α-(phenylthio)amidine precursor 16 by reaction with Cu(OTf)2 undergoes cyclocondensation with 1,3-dienes, styrenes, and Β-dicarbonyl compounds to give 1-iminohexahydropyrrolo[1,2-c]pyrimidines having side chains at C3 and C7. In all cases, major products have a cis relationship of the C7 side chain and angular C4a hydrogen, whereas C3 side chains are incorporated with lower stereoselectivity (dr = 2-5:1) in cyclocondensations with dienes and styrenes to give stereoisomer 39 as the major product. In contrast to most cycloadditions of alkenes with N-acyliminium ions, cyclocondensations of alkenes with N-amidinyliminium ions proceed by a stepwise pathway. Cyclocondensation of the cognate ureido aminal 31 with styrene provides the rare 2-imino-5,6-dihydro-4H-1,3-oxazine derivative 32, rather than a pyrimidine as the major product. The high stereoselectivity observed in condensations of 16 with benzyl acetoacetate to afford Biginelli adduct 29 supports the intermediacy of N-amidinyliminium ions in related tethered Biginelli condensations of guanidines reported earlier from our laboratories.
