Dataset Information

Structure Activity Relationships of ?v Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents.

ABSTRACT: Antagonism of ?v?6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an ?v?3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved ?v?6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan ?v antagonists having ca. 100 nM potency against ?v?3, ?v?5, ?v?6, and ?v?8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for ?v?3 and ?v?5.

SUBMITTER: Adams J

PROVIDER: S-EPMC4233353 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structure Activity Relationships of αv Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents.

Adams James J Anderson Edward C EC Blackham Emma E EE Chiu Yin Wa Ryan YW Clarke Thomas T Eccles Natasha N Gill Luke A LA Haye Joshua J JJ Haywood Harvey T HT Hoenig Christian R CR Kausas Marius M Le Joelle J Russell Hannah L HL Smedley Christopher C Tipping William J WJ Tongue Tom T Wood Charlotte C CC Yeung Jason J Rowedder James E JE Fray M Jonathan MJ McInally Thomas T Macdonald Simon J F SJ

ACS medicinal chemistry letters 20140919 11

Antagonism of αvβ6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an αvβ3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved αvβ6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan ...[more]

PMID: 25408832

Similar Datasets

Project description:MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson's disease and schizophrenia. Herein, we report the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [(3)H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q(2) of 0.513, R(2) (ncv) of 0.868, R(2) (pred) = 0.876, while the CoMSIA model yielded a Q(2) of 0.450, R(2) (ncv) = 0.899, R(2) (pred) = 0.735. For activity II study, CoMFA model yielded statistics of Q(2) = 0.5, R(2) (ncv) = 0.715, R(2) (pred) = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R(7), R(3) and position A benefit activity I of the antagonists, but decrease it when projected in R(8) and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3D-QSAR modeling of these mGluR2 antagonists. All the conclusions may lead to a better understanding of the mechanism of antagonism and be helpful in the design of new potent mGluR2 antagonists.

Dataset Information

Structure Activity Relationships of ?v Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents.

Publications

Structure Activity Relationships of αv Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure