1-NM-PP1 br Development of lorlatinib from crizotinib to a c

Development of lorlatinib from crizotinib (1) to a clinical candidate (6) Xalkori (1, PF-02341066, crizotinib), was the first-in-class ALK inhibitor approved by the Unites States Food and Drug Administration (FDA) in 2011 as a first-line treatment for ALK+- NSCLC patients. This section describes the development strategy of lorlatinib (PF-06463922) from compound (1) to its FDA approval as third-generation macrocyclic ROS1 inhibitor with novel chemical scaffold. The strategic development of lorlatinib (6) from crizotinib (1) shown in Scheme 2. To address emerged clinical resistance, significant efficacy benefits, higher tumor intracellular and free 1-NM-PP1 concentrations for superior target modulation of compound (1), an increased in CNS availability was perceived by avoiding transporter-mediated efflux at the BBB and tumor cell surface. To this end, improvement in drug-like properties of compound (1) was surveyed, the structure-based drug designing strategy and optimization of lipophilic efficiency (LipE) were taken as guiding factor [69], [70], [71], [72] and the course of optimization of LipE was monitored by (LipE = pKi (or pIC50) − logD). Furthermore, to achieve desirable ADME and molecular weight intensive investigations were carried out to get the smallest and most potent inhibitor possessing desired drug-like properties including CNS exposure and safe drug profile. To address the issue of clinically resistant mutants and high P-glycoprotein 1 (Pgp) efflux (a permeability glycoprotein), modifications on compound (1) were carried out by installing variety of substituents to give a series of acyclic aminopyridine or aminopyrazine ALK inhibitors. After synthesizing numerous analogs bearing diverse substituents including methoxy, triazoloyl, secondary or tertiary amides at A-ring and variety of substituted C-rings led to the identification of dihydroxyaminopyridine 2 (PF-06439015) with improved wild-type potency (pALK cell IC50 = 0.76 nM, 105-fold than 1) and gatekeeper mutant (pALK-L1196 M cell IC50 = 6.6 nM, 128-fold than 1) with robust in vivo efficacy, acceptable LipE (5.3), and high efflux potential (MDR BA/AB = 30.6/2.8, ratio 10.9) due to inherited excess hydrogen bond donors (HBD) and polarity [73]. In kinase selectivity profile assay against 207 kinases more than 80% inhibition (at 1 μM dose) was exhibited for 33 off-target kinases and dihydroxy (2) revealed as very potent ROS1 inhibitor (Ki = 0.02 nM). PF-06439015 (2) emerged as a potent (wt 3T3-EML4-ALK IC50 = 0.76 nM, 100-fold than 1) and remained impressive across a broad panel of engineered ALK mutant cell lines including L1196 M (IC50 = 6.6 nM), G1269A (IC50 = 9.0 nM), S1206Y (IC50 = 4.5 nM), C1156Y (IC50 = 0.6 nM), F1174L (IC50 = 0.2 nM), L1152R (IC50 = 3.5 nM), 1151Tins (IC50 = 24 nM) and revealed 67−825-fold increment in potency compared to crizotinib (1). Preclinical rat pharmacokinetic (PK) data of compound (2) demonstrated moderate-to-high in vivo at plasma clearance, modest volume of distribution, reasonable half-life, and 86% bioavailability. Furthermore, compound (2) showed tumorstasis (100%TGI) inhibition in a crizotinib-resistant (H3122-L1196 M) at lower dose and the highest dose (50 mg/kg b.i.d) showed significant tumor growth regression (56%) without significant body weight loss in a mouse tumor xenograft study. Although property oriented, structure-based and lipophilic-efficiency-focused drug designing efforts concluded in a more potent, relatively permeable, and metabolically stable another acyclic second generation aminopyridine as ALK inhibitors (2) (PF-06439015). Despite the imperious results, the development of acyclic analogs was further limited due to low MDR BA/AB ratios (<2.5) to afford the better permeability required to attain efficacious exposures in the CNS and the difficulty in overlapping potency (L1196 M IC50 < 25 nM). However, revealed key structural facts regarding protein ligand interactions facilitated the designing horizon of ligands with improved binding affinity and efficiency. In this context, construction of macrocycle-based inhibitors driven by LipE and MW optimization to provide desirable CNS and ADME properties with acceptable clinical potency was envisioned and two general designs [74], [75], [76], [77], [78], [79] were pursued to control conformations for further optimization.