Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor

Abstract

ABSTRACT:The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. By using aminopyrazoles as aniline bioisosteres, we discovered a novel series of LRRK2 inhibitors. Herein, we describe our optimization effort that resulted in the identification of a highly potent, brain-penetrant aminopyrazole LRRK2 inhibitor (18) that addressed the liabilities (e.g., poor solubility and metabolic soft spots) of our previously disclosed anilinoaminopyrimidine inhibitors. In in vivo rodent PKPD studies, 18 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration. The strategies of bioisosteric substitution of aminopyrazoles for anilines and attenuation of CYP1A2 inhibition described herein have potential applications to other drug discovery programs. KEYWORDS: LRRK2, kinase inhibitor, Parkinson's disease, CYP1A2 inhibition P arkinson's disease (PD) is a neurodegenerative disorder that affects approximately 1% of the world's population over the age of 65. 1 Identification of a disease-modifying or neuroprotective therapeutic for PD patients remains a significant challenge. Recently, genetic research has revealed a connection between a missense mutation (G2019S) in the leucine-rich repeat kinase 2 (LRRK2) gene and a number of familial and idiopathic PD cases. 2−9 Significantly, multiple reports have shown that this mutation enhances the kinase activity of LRRK2. 10−17 The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has therefore been proposed as a potential treatment for PD. 18−23 We recently reported the first disclosure of a series of highly potent, selective, and brain-penetrable anilino-pyrimidine LRRK2 inhibitors as exemplified by compound 1. 22,23 Examination of the liabilities of 1 and structurally similar analogues revealed (a) moderate to poor aqueous solubility (thermodynamic solubility of 1 at pH 7.4 < 0.9 μg/mL), (b) potential for ortho-quinoneimine reactive metabolite formation, and (c) a morpholinocarboxamide motif as a major site of metabolism as indicated by metabolite identification studies (MetID). In an effort to improve upon 1 and mitigate potential safety risks, we initiated a campaign to identify a suitable bioisosteric replacement for the aniline functionality. This approach resulted in the discovery of a novel series of highly selective aminopyrazole LRRK2 inhibitors.Docking experiments using a JAK-2-derived homology model of LRRK2 suggested that compound 1 binds in the ATP binding site of LRRK2 as shown in Figure 1. 22,23 In designing anilino-carboxamide replacements, we chose to retain the hinge binding diaminopyrimidine core as well as the C-5 trifluoromethyl group that interacts favorably with the methionine gatekeeper through van der Waal contacts. Additionally, our lead optimization efforts toward 1 established the importance of occupying the vector adjacent to the hingebinding anilino N-H motif (methoxy group in...

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

“…Chan et al identified a new aminopyrazole as a Leucine-Rich Repeat Kinase 2 (LRRK2) inhibitor. In in vivo rodent PKPD studies, compound 489 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration [ 383 ]. 4-(1-Phenyl-1 H -pyrazol-4-yl)quinoline 490 was identified by screening the Lundbeck compound collection, and characterized as having mGlu4 receptor positive allosteric modulator properties.…”

Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy

“…Analog 24 was >35-fold selective for CDK2/5 over CDK9. We also screened 24 against a panel of other kinases inhibited by analogs with the aminopyrazole core (Aurora A, 29 Aurora B, DLK/MAP3K12, ITK, 30 JAK2, 31 JNK3, 32 LRRK2, 33 P38a/MAPK14, 32 PAK1, 34 TRKA). Remarkably the IC 50 value for the entire panel was > 10μM, indicating that analog 24 was selective for CDK2, and CDK5 (Table 2).…”

Fluorine-18 Patents (2009–2015). Part 1: Novel Radiotracers

“…Some genes have been identified with the development of Lewy bodies: α-synuclein (SNCA), ubiquitin C-terminal hydrolase like 1 (UCH-L1), parkin (PRKN), leucine rich repeat kinase (LRRK 2), PTENinduced putative kinase 1 (PINK 1) and protein deglycase DJ-1 (also known as Parkinson disease protein 7) [25]. Increased activity of LRRK2 has been associated with hereditary PD; Roche has been investigating small molecule modulators of LRRK2 activity in search of both therapeutics and imaging agents (8-14, Figure 5) [26][27][28]. Unfortunately, no imaging or in vitro binding data of labeled compounds has been published to date.…”