title: Design and synthesis of a novel pyrrolidinyl pyrido pyrimidinone derivative as a potent inhibitor of PI3Kα and mTOR.
abstract: Lead optimization efforts that employed structure base drug design and physicochemical property based optimization leading to the discovery of a novel series of 4-methylpyrido pyrimidinone (MPP) are discussed. Synthesis and profile of 1, a PI3Kα/mTOR dual inhibitor, is highlighted.
authors: Cancer Chemistry, Pfizer Worldwide Research & Development, La Jolla Laboratories, Pfizer Inc., La Jolla, CA 92121, United States. phuong.le@pfizer.com
authors: Phuong T
authors: PT
authors: Le
authors: Hengmiao
authors: H
authors: Cheng
authors: Sacha
authors: S
authors: Ninkovic
authors: Michael
authors: M
authors: Plewe
authors: Xiaojun
authors: X
authors: Huang
authors: Hai
authors: H
authors: Wang
authors: Shubha
authors: S
authors: Bagrodia
authors: Shaoxian
authors: S
authors: Sun
authors: Daniel R
authors: DR
authors: Knighton
authors: Caroline M
authors: CM
authors: LaFleur Rogers
authors: Andrew
authors: A
authors: Pannifer
authors: Samantha
authors: S
authors: Greasley
authors: Deepak
authors: D
authors: Dalvie
authors: Eric
authors: E
authors: Zhang
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D011744:Pyrimidinones; D011759:Pyrrolidines; D058570:TOR Serine-Threonine Kinases; C032519:pyrrolidine