Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2

Abstract

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators

“…X-ray structures of the complexes of 56 with JAK1 and JAK2 (Figure 25c,d) demonstrated that the C-2 (R)-hydroxyethyl moiety interacts differently with the Glu966 and Asp939 residues, accounting for the remarkable selectivity. 59 Compounds 57 and 58, two initial leads with the 5H-pyrrolo[2, 3-b]pyrazine scaffold, were potent ATP-competitive inhibitors of JAKs but lacked selectivity among JAK isoforms. It was recognized that a cysteine residue (Cys909) in JAK3 is replaced by serine at the same position in both JAK1 and JAK2.…”

LEADOPT: An automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors

“…JAK1 is a key intracellular mediator of helical cytokine signaling pathways, which plays a central role in inflammation, immune function and hematopoiesis [35]. Very recently, Zak et al reported a series of selective JAK1 inhibitors and the crystal structure of JAK1 in complex with an inhibitor (T1), 2-methyl-1-(piperidin-4-yl)-1,6-dihydroimidazo [4,5-d]pyrrolo [2,3-b]pyridine (PDB code: 4EHZ) [35].…”

“…Very recently, Zak et al reported a series of selective JAK1 inhibitors and the crystal structure of JAK1 in complex with an inhibitor (T1), 2-methyl-1-(piperidin-4-yl)-1,6-dihydroimidazo [4,5-d]pyrrolo [2,3-b]pyridine (PDB code: 4EHZ) [35]. In this case study, we tried to use LEADOPT to perform structural modifications for T1.…”

Selective JAK Inhibitors

“…By minimizing JAK2 activity, it was expected that the side effects seen with JAK2 therapies, such as anemia, could be reduced in patients. In a number of detailed publications, a series of imidazopyrrolopyridines were described [25][26][27]. Starting from tofacitinib (1) [28], a modeling analysis revealed that the syn-periplaner (syn-1) binding conformation was distinct from the lower energy antiperiplanar conformation (anti-1; Figure 1).…”

“…Compound 8, the direct 2-methyl analog of 7, was not only more potent (JAK1 IC 50 = 10 nM), but displayed an impressive selectivity over JAK2 of 20-fold, albeit with low permeability [26,27]. Crystal structure future science group Review Dymock, Yang, Chu-Farseeva & Yao analysis supports the explanation that a close contact of 3.2 Å between the 2-methyl of 8 and Glu-966 is responsible for the observed selectivity.…”