The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structure-activity relationships.
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.
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA 92697-2025, United States.
Michael B
MB
Shaghafi
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States.
David G
DG
Barrett
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States.
Francis S
FS
Willard
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA 92697-2025, United States. Electronic address: leoverma@uci.edu.
Larry E
LE
Overman
D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005947:Glucose / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010641:Phenotype; D011083:Polycyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D006146:Guanidines; D007328:Insulin; D011083:Polycyclic Compounds; D005947:Glucose
Diabetes; Guanidine; Insulin secretogogue