Potent and selective Bruton’s tyrosine kinase inhibitors: Discovery of GDC-0834

Abstract

SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors.

Discovery of highly potent and selective Bruton’s tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability

“…In a few cases, we synthesized the individual (R) enantiomer directly as the required chiral intermediate was available from the synthesis of GDC-0834. 6 In the case of 15, we were able to assign the (S) configuration after 16 (R) was unambiguously synthesized and a racemic mixture of 15 and 16 was resolved by SFC. The sense of chirality of each analog is noted in Table 1.…”

“…Bruton's tyrosine kinase (BTK) plays a critical role in the development, differentiation and proliferation of B-lineage cells, making it an attractive target for the treatment of immunological disorders such as rheumatoid arthritis (RA), lupus, and multiple sclerosis (MS) [1][2][3][4] , as well as B-cell malignancies. 5 As outlined in the preceding papers, [6][7] we identified GDC-0834 (1) as a highly potent and selective inhibitor of BTK with acceptable pharmacokinetic (PK) and safety profiles in preclinical species.…”

“…The first was to remove the labile acyclic amide entirely and replace it with common isosteres or alternate linkers such as -NHSO 2 -, -SO 2 NH-, -NHCHCF 3 -, -CONH-, and -NMeCO-. Unfortunately, all such modifications on the GDC-0834 (1) scaffold or earlier tool molecules produced analogs with dramatically reduced potency, likely due to a change in the ligand conformation or disrupting the interaction with K430, 6 so this endeavor was quickly abandoned. The second strategy involved adding steric bulk around the acyclic amide to potentially hinder amide cleavage.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…To improve the PK properties of the existing potent and selective Btk inhibitor CGI‐1746 ( 92 ), structure‐based design efforts were focused on both the solvent‐exposed region (the morpholine–amide extends into the solvent) and the H3 binding pocket; this study led to the clinical candidate GDC‐0834 ( 93 ), which kept the potency and selectivity of CGI‐1746, but showed significantly improved preclinical PK profiles (oral bioavailability (F) = 35%) (Figure D) …”

“…74 To improve the PK properties of the existing potent and selective Btk inhibitor CGI-1746 (92), structure-based design efforts were focused on both the solvent-exposed region (the morpholine-amide extends into the solvent) and the H3 binding pocket; this study led to the clinical candidate GDC-0834 (93), which kept the potency and selectivity of CGI-1746, but showed significantly improved preclinical PK profiles (oral bioavailability (F) = 35%) ( Figure 17D). 75 The 7-and 8-positions on the benzoxazepinone core of receptor interacting protein 1 (RIP1) kinase inhibitor 94 are exposed to the solvent-accessible region. Consequently, optimization of the center platform and careful modification of neighboring substituents by utilizing structure-based design resulted in the identification of the cyanosubstituted derivative 95 as a highly active and brain-penetrating RIP1 kinase inhibitor with favorable oral bioavailability and excellent ADMET properties (t 1/2 = 210 minutes, in human and mouse liver microsomes; high plasma exposure (AUC = 658 ng/h/mL) and a moderate plasma duration (mean residence time, MRT = 3.1 hour in mice) ( Figure 17E).…”