ABSTRACT
The progesterone receptor is able to bind to a large number and variety of ligands that elicit a broad range of transcriptional responses ranging from full agonism to full antagonism and numerous mixed profiles inbetween. We describe here two new progesterone receptor ligand binding domain x-ray structures bound to compounds from a structurally related but functionally divergent series, which show different binding modes corresponding to their agonistic or antagonistic nature. In addition, we present a third progesterone receptor ligand binding domain dimer bound to an agonist in monomer A and an antagonist in monomer B, which display binding modes in agreement with the earlier observation that agonists and antagonists from this series adopt different binding modes.
Subject(s)
Receptors, Progesterone/agonists , Receptors, Progesterone/antagonists & inhibitors , Receptors, Progesterone/metabolism , Animals , Binding Sites , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray/methods , Dimerization , Drug Design , Drug Evaluation, Preclinical , Ligands , Mifepristone/chemistry , Models, Molecular , Molecular Conformation , Norethindrone/chemistry , Progesterone/chemistry , Protein Binding , Protein ConformationABSTRACT
Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.
Subject(s)
Amines/chemistry , Isoquinolines/chemistry , Piperidines/chemistry , Protein Kinase Inhibitors/chemistry , Quinolones/chemistry , rho-Associated Kinases/antagonists & inhibitors , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/therapeutic use , Amines/chemical synthesis , Amines/therapeutic use , Animals , Disease Models, Animal , Hypertension/drug therapy , Models, Chemical , Models, Molecular , Piperidines/chemical synthesis , Piperidines/therapeutic use , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Quinolones/chemical synthesis , Quinolones/therapeutic use , Rats , Structure-Activity Relationship , rho-Associated Kinases/metabolismABSTRACT
Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
Subject(s)
Amines/chemistry , Isoquinolines/chemistry , Protein Kinase Inhibitors/chemistry , rho-Associated Kinases/antagonists & inhibitors , Amines/chemical synthesis , Amines/pharmacokinetics , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Drug Evaluation, Preclinical , Isoquinolines/chemical synthesis , Isoquinolines/pharmacokinetics , Mice , Mice, Inbred C57BL , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , rho-Associated Kinases/metabolismABSTRACT
High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.
