Design,Synthesis And Evaluation Of Novel A_2A Inhibitors And Novel Hedgehog/PI3K Dual Inhibitors

The thesis is made of two sections.The first section:design,synthesis and evaluation of novel A_2A inhibitors for the treatment of Parkinson's disease?PD?.Parkinson's disease?PD?,which is the second neurodegenerative disease in the world,is characterized by the motor symptoms of rest tremor,bradykinesia,rigidity and non-motor symptoms of depression and cognitive disorders.The pathology of PD is the greatly reduced activity of dopamine-secreting cells caused by cell-death in substantia nigra pars compacta region.Current therapies are mainly based on dopaminergic replacement strategies by diagnosis either dopamine agonists or dopamine forebody like lecodopa.These treatments just relieve the symptoms and have no effect on slowing or stopping the disease progression.Diminished efficacy,motor fluctuation and dyskinisia will occur during long-term usage of these drugs.In the past decade,A_2A receptor has emerged as a great potential target among nondopaminergic strategies for treatment of PD.Istradefylline?KW-6002?,one of most advanced A_2A receptor antagonist in clinical development,is launched in Japanese market on March 25,2013.However,poor solubility is a common issue because of the adenosine or adenosine analogue skeleton.For instance,Preladenant is reported to have solubility of less than 10 ng/mL at pH=7.4.Our lab was focused on 2,4,6-trisubstituted pyrimidines in pursuit of novel A_2A receptor antagonist for the treatment of PD.At first,we use a bioisosteric replacement of potentially labile acetamide group to design and synthesize a series of compounds.Compounds show improved potency?1.1 nM?and chemical stability.Unfortunately,when we subjected these compounds to a preliminary CYP inhibition test,they demonstrated80%inhibition of CYP3A4 at 10?M concentration.We hypothesized that the high CYP inhibition was a result of a high lipopholicity?cLogP=3.29?.So we designed and synthesized a new series of compounds with less lipophilicity.The most potential compound demonstrated a high receptor binding affinity(hA_2A=0.22nM).It also showed limited liver safety.Although the metabolic stability in mouse live microsomes was suboptimal(t_1/2=3.6 min),the compound could readily crossed the BBB and demonstrated dose proportional exposure in striatum when dosed i.p..More importantly,the compound exhibited significant reversal of haloperidol induced catalepsy?10 mg/kg?.In order to understand the interaction patterns,we conducted computer-aided drug design.According to three-dimensional pharmacophore model,we decided to remove the acetamide group and add cyano on 5 position of pyrimidine core and foster favorable interactions with nearby residues.Compounds from this new pharmacophore exhibited high potency?1 nM?;low cytochrome P450 inhibition?inbibition<12%,con.=10?M?;desirable clearance(t_1/2?20 min).When dosed orally as low as 10 mg/kg,the compound exhibited excellent reversal of the haloperidol induced catalepsy.The second section:design,synthesis and evaluation Hedgehog/PI3K dual inhibitor.Hedgehog?Hh?signaling pathway plays an important role in regulating cell multiplication and differentiation during embryonic development during embryonic development.Aberrant activation of Hh signaling pathway leads to abnormality like tumor formation,including medulloblastoma and basal cell carcinoma.The Smoothened?SMO?receptor is an important role in Hh signaling pathway.SMO inhibitors has emerged as a highlight in pharmaceutical companies to block Hh pathway for treating oncology.Among the compounds,Vismodegib and Sonidegib achieved the FDA approval in 2012 and 2015respectively for treatment of adult patients with basal cell carcinoma.Similar as most cancer therapies,Vismodegib occurred resistance even during clinical development.Later analysis demonstrated that codon 473 from Asp to His leading the lost binding of mutated Smo of Vismodegib.Numerous mouse model found that simultaneous blockage of Hh and PI3K pathways resulted in tumor regression compared with single agent along.Meanwhile,combination therapy is also an efficient way to overcome tumor resistance.The dual Hedgehog and PI3K inhibitor represented a promising approach in drug discovery.We designed and synthesized a series of compounds by a scaffold hybridization strategy from a known SMO antagonist.We finally discovered several potent SMO inhibitors as well as decent PI3K inhibitors.For example,one?PK-03?possessed the activity of 41 nM and 980 nM for SMO and PI3K respectively.Thus,the pharmacophore——6-?pyridin-3-yl-?benzi[d]thiazole could serve as a lead to optimize dual Hh and PI3K inhibitors.